Beta-lactamase inhibitors

ABSTRACT

Described herein are compounds and compositions that modulate the activity of beta-lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/577,278, filed Sep. 20, 2019, now abandoned, which is a continuationof U.S. patent application Ser. No. 16/375,575, filed Apr. 4, 2019,which is a continuation of U.S. patent application Ser. No. 16/103,445,filed Aug. 14, 2018, now abandoned, which is a continuation of U.S.patent application Ser. No. 15/675,262, filed Aug. 11, 2017, and issuedas U.S. Pat. No. 10,125,152 on Nov. 13, 2018, which is a continuation ofU.S. patent application Ser. No. 15/194,433, filed Jun. 27, 2016, andissued as U.S. Pat. No. 9,771,382 on Sep. 26, 2017, which is acontinuation of U.S. patent application Ser. No. 14/759,853, filed Jul.8, 2015, and issued as U.S. Pat. No. 9,403,850 on Aug. 2, 2016, which isa U.S. National Stage entry of International Application No.PCT/US2014/011144, filed Jan. 10, 2014, which claims the benefit ofpriority of U.S. Provisional Patent Application No. 61/751,161, filedJan. 10, 2013, and U.S. Provisional Patent Application No. 61/783,261,filed Mar. 14, 2013, all of which are hereby incorporated by referencein their entirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with the government support under Grant numbersR43AI096679 awarded by the National Institutes of Health (NIH),R43AI096613 awarded by the National Institutes of Health (NIH), andR01AI089512 awarded by the National Institutes of Health (NIH). Thegovernment has certain rights in the invention.

FIELD OF INVENTION

The present invention relates to boron-containing compounds,compositions, preparations and their use as inhibitors of beta-lactamaseenzymes and as antibacterial agents.

BACKGROUND OF THE INVENTION

Antibiotics are the most effective drugs for curing bacteria-infectiousdiseases clinically. They have a wide market due to their advantages ofgood antibacterial effect with limited side effects. Among them, thebeta-lactam class of antibiotics (for example, penicillins,cephalosporins, and carbapenems) are widely used because they have astrong bactericidal effect and low toxicity.

To counter the efficacy of the various beta-lactams, bacteria haveevolved to produce variants of beta-lactam deactivating enzymes calledbeta-lactamases, and in the ability to share this tool inter- andintra-species. These beta-lactamases are categorized as “serine” or“metallo” based, respectively, on presence of a key serine or zinc inthe enzyme active site. The rapid spread of this mechanism of bacterialresistance can severely limit beta-lactam treatment options in thehospital and in the community.

SUMMARY OF THE INVENTION

Described herein are compounds that modulate the activity ofbeta-lactamases. In some embodiments, the compounds described hereininhibit beta-lactamases. In certain embodiments, the compounds describedherein are useful in the treatment of bacterial infections.

In one aspect, provided herein are compounds of Formula I or Formula Ia,or pharmaceutically acceptable salts, polymorphs, solvates, tautomers,metabolites, or N-oxides thereof:

wherein:

-   -   M is a bond, —O—, —S—, —S(O)—, SO₂—, or —N(R⁴)—;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;        -   provided that            -   when n is 0, then M is a bond;    -   p is 2, 3, 4 or 5;    -   X¹ and X² are independently selected from —OH, —OR⁸, or F;    -   Z is >C═O, >C═S, or >SO₂;    -   ArA is an aromatic or heteroaromatic ring system optionally        substituted with one or more substituents from the group        consisting of fluoro, chloro, bromo, —CN, optionally substituted        C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl, optionally        substituted heterocycle, optionally substituted aryl, optionally        substituted heteroaryl, —OH, —OR¹⁰, and —SR¹⁰;    -   each Y is selected from the group consisting of        -   —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —O(CR⁶R⁷)_(v)NR⁴R⁵, —S(O)_(0,1,2)(CR⁶R⁷)_(v)NR⁴R⁵,            —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(v)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)OR¹⁰,            —NR⁴(CR⁶R⁷)_(v)S(O)_(0,1,2)R¹⁰, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(═NR⁵)R⁶,            —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —S(O)_(0,1,2)—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶,            —NR⁴SO₂R⁶, —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O)NR⁴R⁵,            —(CR⁶R⁷)_(v)C(O)NR⁴R⁵, —SO₂NR⁴R⁵, -Heteroaryl-NR⁴R⁵,            -Heterocyclyl-NR⁴R⁵, -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —N(R⁴)—Heteroaryl-NR⁴R⁵,            —N(R⁴)—Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl, —(CR⁶R⁷)_(v)Heterocyclyl,            —O-Heteroaryl, —O-Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)Heteroaryl,            —NR⁴(CR⁶R⁷)_(v)Heterocyclyl, —O(CR⁶R⁷)_(v)Heteroaryl,            —O(CR⁶R⁷)_(v)Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)NR⁵-Heteroaryl,            —NR⁴(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,            —O(CR⁶R⁷)_(v)NR⁵-Heteroaryl, —O(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,            —O(CR⁶R⁷)_(v)O-Heterocyclyl, —NR⁴R⁵R⁹⁺Q⁻,            —(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻,            —NR⁴R⁹⁺(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻ ₂, —(CR⁶R⁷)_(v)(T)⁺Q⁻, and            —O(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻;        -   wherein:            -   T is pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl;            -   Q is a pharmaceutically acceptable counterion; and            -   v is 1-4;        -   or two Ys taken together with the carbon atoms to which they            are attached to ArA form an optionally substituted            carbocycle or an optionally substituted heterocycle;    -   R^(a), R^(b), and R^(c) are independently selected from the        group consisting of hydrogen, fluoro, chloro, bromo, optionally        substituted C₁-C₆ alkyl, optionally substituted C₃-C₆        cycloalkyl, optionally substituted heterocyclyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —OR¹⁰,        —NR⁴R⁵, and —SR¹⁰;    -   R¹ and R² are independently selected from the group consisting        of hydrogen, fluoro, chloro, bromo, optionally substituted C₁-C₆        alkyl, optionally substituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰,        —SR¹⁰, and —NR⁴R⁵,        -   or R¹ and R² taken together form an oxo, oxime, or an            optionally substituted carbocycle or optionally substituted            heterocycle with the carbon to which they are attached;    -   R³ is hydrogen, optionally substituted C₁-C₆ alkyl, or a        pharmaceutically acceptable prodrug;    -   R^(d), R⁴ and R⁵ are independently selected from the group        consisting of hydrogen, —OH, —CN, optionally substituted C₁-C₆        alkyl, optionally substituted alkoxyalkyl, optionally        substituted hydroxyalkyl, optionally substituted aminoalkyl,        optionally substituted cycloalkyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkylalkyl,        optionally substituted heterocyclylalkyl, optionally substituted        aralkyl, optionally substituted heteroaralkyl,        (poly-ethylene-glycol)-ethyl, and an optionally substituted        saccharide; or R⁴ and R⁵ taken together form an optionally        substituted heterocycle with the nitrogen to which they are        attached;    -   R⁶ and R⁷ are independently selected from the group consisting        of hydrogen, fluoro, chloro, bromo, optionally substituted C₁-C₆        alkyl, optionally substituted alkoxyalkyl, optionally        substituted hydroxyalkyl, optionally substituted C₃-C₆        cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵, —C(O)NR⁴R⁵,        —NR⁴SO₂R⁵, optionally substituted heterocyclyl, optionally        substituted aryl, and optionally substituted heteroaryl;        -   or R⁶ and R⁷ taken together form an oxo, oxime, or an            optionally substituted carbocycle or an optionally            substituted heterocycle with the carbon to which they are            attached;    -   R⁸ is optionally substituted C₁-C₆ alkyl, optionally substituted        C₃-C₆ cycloalkyl, or a pharmaceutically acceptable boronate        ester group;    -   R⁹ is optionally substituted C₁-C₆ alkyl;    -   R¹⁰ is optionally substituted C₁-C₆ alkyl or optionally        substituted C₃-C₆ cycloalkyl.

In some embodiments of a compound of Formula I or Formula Ia, R^(a),R^(b), and R^(c) are independently selected from the group consisting ofhydrogen, fluoro, chloro, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —NR⁴R⁵, and —SR¹⁰. In certainembodiments, R^(a), R^(b), and R^(c) are independently hydrogen, fluoro,or chloro. In preferred embodiments, R^(a), R^(b), and R^(c) arehydrogen.

In some embodiments of a compound of Formula I or Formula Ia, R³ ishydrogen, methyl, ethyl, propyl, butyl, or isopropyl. In preferredembodiments, R³ is hydrogen.

In some embodiments of a compound of Formula I or Formula Ia, X¹ and X²are —OH.

In some embodiments of a compound of Formula I or Formula Ia, R^(d) ishydrogen or C₁-C₄-alkyl. In preferred embodiments, R^(d) is hydrogen.

In some embodiments of a compound of Formula I or Formula Ia, Z is >C═Oor >SO₂. In preferred embodiments, Z is >C═O.

In some embodiments of a compound of Formula I or Formula Ia, each R¹and R² is independently selected from the group consisting of fluoro,chloro, bromo, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, and —NR⁴R⁵, or R¹ andR² taken together form an oxo, oxime, or an optionally substitutedcarbocycle or optionally substituted heterocycle with the carbon towhich they are attached.

In some embodiments of a compound of Formula I or Formula Ia, ArA isselected from the group consisting of benzene, naphthalene, pyridine,pyrimidine pyrazine, pyridazine, triazine, thiophene, furan, pyrrole,pyrazole, triazole, imidazole, thiazole, isothiazole, oxazole,isoxazole. indole, indazole, azaindole, azaindazole, isoindole,indolizine, imidazopyridine, pyrazolo-pyridine, thiazolo-pyridinepyrrolo-pyrimidine, thieno-pyrazole, benzimidazole, benzothiazole,benzoxazole, benzofuran, benzisoxazole, benzisothiazole, quinoline,isoquinoline, quinoxaline, quinazoline, cinnoline, benzotriazinenapthyridine, pyrido-pyrimidine, pyrido-pyrazine, pyridopyridazine,isoxazolo-pyridine, and oxazolo-pyridine. In certain embodiments ArA isselected from the group consisting of benzene, pyridine, pyrimidine,thiophene, thiazole, triazole, indole, benzimidazole, azaindole,thienopyrazole, quinoline, quinazoline, and quinoxaline. In preferredembodiments, ArA is benzene, thiophene, pyridine, aza-indole, orquinoxaline.

In some embodiments of a compound of Formula I or Formula Ia, at leastone Y is selected from the group consisting of NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵,—C(═NR⁴)NR⁴C(O)R⁶, —NR⁴SO₂R⁶, —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O)NR⁴R⁵,—(CR⁶R⁷)_(v)C(O)NR⁴R⁵, -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,-Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,—N(R⁴)—Heteroaryl-NR⁴R⁵, —N(R⁴)—Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl,—(CR⁶R⁷)_(v)Heterocyclyl, —O-Heteroaryl, —O-Heterocyclyl,—NR⁴(CR⁶R⁷)_(v)Heteroaryl, —NR⁴(CR⁶R⁷)_(v)Heterocyclyl,—O(CR⁶R⁷)_(v)Heteroaryl, —O(CR⁶R⁷)_(v)Heterocyclyl, and—O(CR⁶R⁷)_(v)O-Heterocyclyl. In certain embodiments, at least one Y isselected from the group consisting of —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵,—C(═NR⁴)NR⁴C(O)R⁶, —NR⁴C(O)R⁶, —(CR⁶R⁷)_(v)C(O)NR⁴R⁵,-Heterocyclyl-NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,—N(R⁴)—Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocycyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl,and —NR⁴(CR⁶R⁷)_(v)Heterocycyl. In further embodiments, at least one Yis selected from the group consisting of -Heteroaryl-NR⁴R⁵,-Heterocyclyl-NR⁴R⁵, -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,-Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —N(R⁴)—Heteroaryl-NR⁴R⁵,—N(R⁴)—Heterocyclyl-NR⁴R⁵, -Heteroaryl-C(═NR⁵)NR⁴R⁵,-Heterocyclyl-C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, and—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵. In preferred embodiments, atleast one Y is selected from the group consisting of —NR⁴R⁵,—NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵, —N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)OR¹⁰, —(CR⁶R⁷)_(v)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,NR⁵C(═NR⁵)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁵C(O)CR⁶(NR⁴R⁵)(CR⁶R⁷)_(v)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶,—NR⁴(CR⁶R⁷)_(v)Heteroaryl, and —O(CR⁶R⁷)_(v)NR⁴R⁵. In preferredembodiments, at least one Y is —(CR⁶R⁷)_(v)NR⁴R⁵.

In certain embodiments, two Y groups taken together with the carbonatoms to which they are attached form an optionally substitutedcarbocycle or an optionally substituted heterocycle. In someembodiments, the carbocycle or heterocycle is optionally substitutedwith one to three substituents selected from the group consisting offluoro, chloro, bromo, —CN, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₆ cycloalkyl, optionally substitutedheterocycle, optionally substituted aryl, optionally substitutedheteroaryl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵,—C(═NR⁴)NR⁴R⁵, -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl, and —(CR⁶R⁷)_(v)Heterocyclyl. In certainembodiments, the two Y groups, together with the atoms to which they areattached form a pyrroline or tetrahydropyridine ring. In certainembodiments, the two Y groups, together with the atoms to which they areattached form a pyrroline ring.

In some embodiments, p is 2, 3, or 4. In certain embodiments, p is 2 or3.

In some embodiments of a compound of Formula I or Formula Ia, R⁴ and R⁵are independently selected from the group consisting of hydrogen, —OHoptionally substituted C₁-C₆ alkyl, optionally substituted alkoxyalkyl,optionally substituted hydroxyalkyl, and optionally substitutedheterocyclyl. In preferred embodiments, R⁴ and R⁵ are independentlyhydrogen or optionally substituted C₁-C₆ alkyl. In certain embodiments,R⁴ and R⁵ are hydrogen.

In some embodiments of a compound of Formula I or Formula Ia, each R⁶and R⁷ is independently selected from the group consisting of hydrogen,optionally substituted C₁-C₆ alkyl, —OH, —NR⁴R⁵, and optionallysubstituted heterocyclyl, or R⁶ and R⁷ taken together form an optionallysubstituted heterocycle with the carbon to which they are attached. Inpreferred embodiments, each R⁶ and R⁷ is independently hydrogen, fluoro,or optionally substituted C₁-C₆ alkyl. In some embodiments, R⁶ and R⁷are hydrogen. In some preferred embodiments, v is 1.

In some embodiments of a compound of Formula I or Formula Ia, thecompound comprises at least one basic amine. In some embodiments, thecompound comprises at least two basic amines.

In certain embodiments of a compound of Formula I or Formula Ia, thecompound is selected from the group represented by the followingstructures:

or a pharmaceutically acceptable salt, solvate, polymorph, stereoisomer,tautomer, prodrug, metabolite, N-oxide, or isomer thereof, wherein thecompound is present in a closed, cyclic form according to Formula I andas shown in the structures above, an open, acyclic form according toFormula Ia, or mixtures thereof.

In some embodiments, the compound of Formula I or Formula Ia is thestereoisomer represented by any of the structures shown herein. In someembodiments, the compound of Formula I or Formula Ia is an enantiomer ofthe stereoisomer represented by any of the structures shown herein. Incertain embodiments, the compound of Formula I or Formula Ia is adiastereomer of the stereoisomer represented by any of the structuresshown herein. In some embodiments, the compound of Formula I or FormulaIa is a mixture of enantiomers and/or diastereomers of the stereoisomerrepresented by any of the structures shown herein. In certainembodiments, the compound of Formula I or Formula Ia is a racemate ofthe stereoisomer represented by any of the structures herein.

In another aspect, provided herein are pharmaceutical compositionscomprising a compound Formula I or Formula Ia as described herein, or apharmaceutically acceptable salt, polymorph, solvate, prodrug, N-oxide,or isomer thereof, and a pharmaceutically acceptable excipient. In someembodiments, the pharmaceutical composition further comprises abeta-lactam antibiotic. In certain embodiments, the beta-lactamantibiotic is a penicillin, cephalosporin, carbapenem, monobactam,bridged monobactam, or a combination thereof.

In an additional aspect, provided herein are methods of treating abacterial infection in a subject, comprising administering to thesubject a compound of Formula I or Formula Ia as described herein incombination with a therapeutically effective amount of beta-lactamantibiotic.

In a further aspect, provided herein are methods of treating a bacterialinfection in a subject, comprising administering to the subject apharmaceutical composition as described herein, optionally incombination with a beta-lactam antibiotic. In certain embodiments, themethods for treating a bacterial infection in a subject compriseadministering to the subject a pharmaceutical composition as describedherein in combination with a beta-lactam antibiotic.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

Beta-lactamases are typically grouped into 4 classes: Ambler classes A,B, C, and D, based on their amino acid sequences. Enzymes in classes A,C, and D are active-site serine beta-lactamases, while class B enzymesare Zn-dependent. Newer generation cephalosporins and carbapenems weredeveloped partly based on their ability to evade the deactivating effectof the early serine-based beta-lactamase variants. However, a recentsurge in new versions of serine-based beta-lactamases—for example ClassA Extended-Spectrum Beta-Lactamase (ESBL) enzymes, Class Acarbapenemases (e.g. KPC-2), chromosomal and plasmid mediated Class Ccephalosporinases (AmpC, CMY, etc.), and Class D oxacillinases—as wellas Class B metallo-beta-lactamases (e.g. VIM, NDM) has begun to diminishthe utility of the beta-lactam antibiotic family, including the morerecent generation beta-lactam drugs, leading to a serious medicalproblem. Indeed the number of catalogued serine-based beta-lactamaseshas exploded from less than ten in the 1970s to over 750 variants (see,e.g., Jacoby & Bush, “Amino Acid Sequences for TEM, SHV and OXAExtended-Spectrum and Inhibitor Resistant β-Lactamases”, on the LaheyClinic website).

The commercially available beta-lactamase inhibitors (clavulanic acid,sulbactam, tazobactam) were developed to address the beta-lactamasesthat were clinically relevant in the 1970s and 1980s (e.g.penicillinases). These beta-lactamase inhibitors are poorly activeagainst the diversity of beta-lactamse enzymes (both serine- andmetallo-based) now emergin clinically. In addition, these enzymeinhibitors are available only as fixed combinations with penicillinderivatives. No combinations with cephalosporins (or carbapenems) areclinically available. This fact, combined with the increased use ofnewer generation cephalosporins and carbapenems, is driving theselection and spread of the new beta-lactamase variants (ESBLs,carbapenemases, chromosomal and plasmid-mediated Class C, Class Doxacillinases, etc.). While maintaining good inhibitory activity againstESBLs, the legacy beta-lactamase inhibitors are largely ineffectiveagainst the new Class A and Class B carbapenemases, against thechromosomal and plasmid-mediated Class C cephalosporinases and againstmany of the Class D oxacillinases.

To address this growing therapeutic vulnerability, and because there arethree major molecular classes of serine-based beta-lactamases, and onemajor class of metallo-beta-lactamases, and each of these classescontain significant numbers of beta-lactamase variants, we haveidentified an approach for developing novel beta-lactamase inhibitorswith broad spectrum functionality. In particular, we have identified anapproach for developing compounds that are active against both serine-and metallo-based beta-lactamase enzymes. Compounds of the currentinvention demonstrate potent activity across all four major classes ofbeta-lactamases.

The present invention is directed to certain boron-based compounds(boronic acids and cyclic boronic acid esters) which are beta-lactamaseinhibitors and antibacterial compounds. The compounds and theirpharmaceutically acceptable salts are useful alone and in combinationwith beta-lactam antibiotics for the treatment of bacterial infections,particularly antibiotic resistant bacterial infections. Some embodimentsinclude compounds, compositions, pharmaceutical compositions, use andpreparation thereof.

Definitions

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment. Thus, the appearances of the phrases “in one embodiment” or“in an embodiment” in various places throughout this specification arenot necessarily all referring to the same embodiment. Furthermore, theparticular features, structures, or characteristics may be combined inany suitable manner in one or more embodiments. Also, as used in thisspecification and the appended claims, the singular forms “a,” “an,” and“the” include plural referents unless the content clearly dictatesotherwise. It should also be noted that the term “or” is generallyemployed in its sense including “and/or” unless the content clearlydictates otherwise.

The term “antibiotic” refers to a compound or composition whichdecreases the viability of a microorganism, or which inhibits the growthor proliferation of a microorganism. The phrase “inhibits the growth orproliferation” means increasing the generation time (i.e., the timerequired for the bacterial cell to divide or for the population todouble) by at least about 2-fold. Preferred antibiotics are those whichcan increase the generation time by at least about 10-fold or more(e.g., at least about 100-fold or even indefinitely, as in total celldeath). As used in this disclosure, an antibiotic is further intended toinclude an antimicrobial, bacteriostatic, or bactericidal agent.Examples of antibiotics suitable for use with respect to the presentinvention include penicillins, cephalosporins and carbapenems.

The term “β-lactam antibiotic” refers to a compound with antibioticproperties that contains a β-lactam functionality. Non-limiting examplesof β-lactam antibiotics useful with respect to the invention includepenicillins, cephalosporins, penems, carbapenems, and monobactams.

The term “β-lactamase” denotes a protein capable of inactivating aβ-lactam antibiotic. The β-lactamase can bean enzyme which catalyzes thehydrolysis of the β-lactam ring of a β-lactam antibiotic. Of particularinterest herein are microbial β-lactamases. The β-lactamase may be, forexample, a serine β-lactamase or a metallo-β-lactamase. β-Lactamases ofinterest include those disclosed in an ongoing website that monitorsbeta-lactamase nomenclature (www.lahey.org) and in Bush, K and G. AJacoby. 2010. An updated functional classification of s-lactamases.Antimicrob. Agents Chemother. 54:969-976. β-Lactamases of particularinterest herein include β-lactamases found in bacteria such as class As-lactamases including the SHV, CTX-M and KPC subclasses, class Bβ-lactamases such as VIM, class C β-lactamases (both chromosomal andplasmid-mediated), and class D β-lactamases. The term “β-lactamaseinhibitor” refers to a compound which is capable of inhibitingβ-lactamase activity. Inhibiting β-lactamase activity means inhibitingthe activity of a class A, B, C, or D β-lactamase. For antimicrobialapplications inhibition at a 50% inhibitory concentration is preferablyachieved at or below about 100 micrograms/mL, or at or below about 50micrograms/mL, or at or below about 25 micrograms/mL. The terms “classA”, “class B”, “class C”, and “class D” β-lactamases are understood bythose skilled in the art and are described in Bush, K and G. A Jacoby.2010. An updated functional classification of β-lactamases. Antimicrob.Agents Chemother. 54:969-976.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“Amino” refers to the —NH₂ radical.

“Cyano” or “nitrile” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Oxime” refers to the ═N—OH substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain saturated hydrocarbon monoradicalhaving from one to about ten carbon atoms, more preferably one to sixcarbon atoms, wherein an sp3-hybridized carbon of the alkyl residue isattached to the rest of the molecule by a single bond. Examples include,but are not limited to methyl, ethyl, n-propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyland hexyl, and longer alkyl groups, such as heptyl, octyl and the like.Whenever it appears herein, a numerical range such as “C₁-C₆ alkyl” or“C₁₋₆ alkyl”, means that the alkyl group may consist of 1 carbon atom, 2carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbonatoms, although the present definition also covers the occurrence of theterm “alkyl” where no numerical range is designated. Unless statedotherwise specifically in the specification, an alkyl group may beoptionally substituted as described below, for example, with oxo, amino,nitrile, nitro, hydroxyl, alkyl, alkylene, alkynyl, alkoxy, aryl,cycloalkyl, heterocyclyl, heteroaryl, and the like.

“Alkenyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon double-bonds and having from two to about tencarbon atoms, more preferably two to about six carbon atoms, wherein ansp2-hybridized carbon of the alkenyl residue is attached to the rest ofthe molecule by a single bond. The group may be in either the cis ortrans conformation about the double bond(s), and should be understood toinclude both isomers. Examples include, but are not limited to ethenyl(—CH═CH₂), 1-propenyl (—CH₂CH═CH₂), isopropenyl [—C(CH₃)═CH₂], butenyl,1,3-butadienyl and the like. Whenever it appears herein, a numericalrange such as “C₂-C₆ alkenyl” or “C₂₋₆ alkenyl”, means that the alkenylgroup may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5carbon atoms or 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkenyl” where no numerical range isdesignated.

“Alkynyl” refers to an optionally substituted straight-chain oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon triple-bonds and having from two to about tencarbon atoms, more preferably from two to about six carbon atoms.Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl,1,3-butadiynyl and the like. Whenever it appears herein, a numericalrange such as “C₂-C₆ alkynyl” or “C₂₋₆ alkynyl”, means that the alkynylgroup may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5carbon atoms or 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkynyl” where no numerical range isdesignated.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain. Unless stated otherwise specifically in thespecification, an alkylene group may be optionally substituted asdescribed below.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted asdescribed below.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising hydrogen, 6 to 30 carbon atoms and at least one aromaticring. The aryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl radicals include, but are not limited to, aryl radicalsderived from the hydrocarbon ring systems of aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals that are optionally substituted.

“Cycloalkyl” or “carbocycle” refers to a stable, non-aromatic,monocyclic or polycycic carbocyclic ring, which may include fused orbridged ring systems, which is saturated or unsaturated. Representativecycloalkyls or carbocycles include, but are not limited to, cycloalkylshaving from three to fifteen carbon atoms, from three to ten carbonatoms, from three to eight carbon atoms, from three to six carbon atoms,from three to five carbon atoms, or three to four carbon atoms.Monocyclic cycloalkyls or carbocycles include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.Polycycic cycloalkyls or carbocycles include, for example, adamantyl,norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane,cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane,and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise statedspecifically in the specification, a cycloalkyl or carbocycle group maybe optionally substituted. Illustrative examples of cycloalkyl groupsinclude, but are not limited to, the following moieties:

and the like.

“Aralkyl” means an -(alkylene)-R radical where R is aryl as definedabove.

“Cycloalkylalkyl” means a -(alkylene)-R radical where R is cycloalkyl asdefined above; e.g., cyclopropylmethyl, cyclobutylmethyl,cyclopentylethyl, or cyclohexylmethyl, and the like.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure. When the fused ring is a heterocyclyl ringor a heteroaryl ring, any carbon atom on the existing ring structurewhich becomes part of the fused heterocyclyl ring or the fusedheteroaryl ring may be replaced with a nitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically inthe specification, a haloalkyl group may be optionally substituted.

“Haloalkoxy” similarly refers to a radical of the formula —OR_(a) whereR_(a) is a haloalkyl radical as defined. Unless stated otherwisespecifically in the specification, a haloalkoxy group may be optionallysubstituted as described below.

“Heterocycloalkyl” or “heterocyclyl” or “heterocyclic ring” or“heterocycle” refers to a stable 3- to 24-membered non-aromatic ringradical comprising 2 to 23 carbon atoms and from one to 8 heteroatomsselected from the group consisting of nitrogen, oxygen, phosphorous andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 12-crown-4,15-crown-5,18-crown-6, 21-crown-7, aza-18-crown-6, diaza-18-crown-6,aza-21-crown-7, and diaza-21-crown-7. Unless stated otherwisespecifically in the specification, a heterocyclyl group may beoptionally substituted. Illustrative examples of heterocycloalkylgroups, also referred to as non-aromatic heterocycles, include:

and the like. The term heterocycloalkyl also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring). Unless stated otherwise specifically in thespecification, a heterocycloalkyl group may be optionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur, and at least one aromatic ring. For purposes ofthis invention, the heteroaryl radical may be a monocycic, bicycic,tricycic or tetracycic ring system, which may include fused or bridgedring systems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group may be optionallysubstituted.

All the above groups may be either substituted or unsubstituted. Theterm “substituted” as used herein means any of the above groups (e.g,alkyl, alkylene, alkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyland/or heteroaryl) may be further functionalized wherein at least onehydrogen atom is replaced by a bond to a non-hydrogen atom substituent.Unless stated specifically in the specification, a substituted group mayinclude one or more substituents selected from: oxo, amino, —CO₂Hnitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, aryl,cycloalkyl, heterocyclyl, heteroaryl, dialkylamines, arylamines,alkylarylamines, diarylamines, trialkylammonium (—N⁺R₃), N-oxides,imides, and enamines; a silicon atom in groups such as trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilylgroups, perfluoroalkyl or perfluoroalkoxy, for example, trifluoromethylor trifluoromethoxy. “Substituted” also means any of the above groups inwhich one or more hydrogen atoms are replaced by a higher-order bond(e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo,carbonyl, carboxyl, and ester groups; and nitrogen in groups such asimines, oximes, hydrazones, and nitriles. For example, “substituted”includes any of the above groups in which one or more hydrogen atoms arereplaced with —NH₂, —NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(═O)OR_(h),—NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g), —SR_(g), —SOR_(g),—SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), and —SO₂NR_(g)R_(h). Inthe foregoing, R_(g) and R_(h) are the same or different andindependently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl,N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/orheteroarylalkyl. In addition, each of the foregoing substituents mayalso be optionally substituted with one or more of the abovesubstituents. Furthermore, any of the above groups may be substituted toinclude one or more internal oxygen, sulfur, or nitrogen atoms. Forexample, an alkyl group may be substituted with one or more internaloxygen atoms to form an ether or polyether group. Similarly, an alkylgroup may be substituted with one or more internal sulfur atoms to forma thioether, disulfide, etc.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined above.Further, an optionally substituted group may be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc). It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (e.g., substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups, potentially ad infinitum) that are stericallyimpractical and/or synthetically non-feasible. Thus, any substituentsdescribed should generally be understood as having a maximum molecularweight of about 1,000 daltons, and more typically, up to about 500daltons.

An “effective amount” or “therapeutically effective amount” refers to anamount of a compound administered to a mammalian subject, either as asingle dose or as part of a series of doses, which is effective toproduce a desired therapeutic effect.

“Treatment” of an individual (e.g. a mammal, such as a human) or a cellis any type of intervention used in an attempt to alter the naturalcourse of the individual or cell. In some embodiments, treatmentincludes administration of a pharmaceutical composition, subsequent tothe initiation of a pathologic event or contact with an etiologic agentand includes stabilization of the condition (e.g., condition does notworsen) or alleviation of the condition. In other embodiments, treatmentalso includes prophylactic treatment (e.g., administration of acomposition described herein when an individual is suspected to besuffering from a bacterial infection).

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The compounds presented herein mayexist as tautomers. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH Some examples of tautomericinterconversions include:

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes, such as, oxidation reactions) by which aparticular substance is changed by an organism. Thus, enzymes mayproduce specific structural alterations to a compound. For example,cytochrome P450 catalyzes a variety of oxidative and reductive reactionswhile uridine diphosphate glucuronyltransferases catalyze the transferof an activated glucuronic-acid molecule to aromatic alcohols, aliphaticalcohols, carboxylic acids, amines and free sulfhydryl groups. Furtherinformation on metabolism may be obtained from The Pharmacological Basisof Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of thecompounds disclosed herein can be identified either by administration ofcompounds to a host and analysis of tissue samples from the host, or byincubation of compounds with hepatic cells in vitro and analysis of theresulting compounds. Both methods are well known in the art. In someembodiments, metabolites of a compound are formed by oxidative processesand correspond to the corresponding hydroxy-containing compound. In someembodiments, a compound is metabolized to pharmacologically activemetabolites.

Compounds

Described herein are compounds that modulate the activity ofbeta-lactamase. In some embodiments, the compounds described hereininhibit beta-lactamase. In certain embodiments, the compounds describedherein are useful in the treatment of bacterial infections. In someembodiments, the bacterial infection is an upper or lower respiratorytract infection, a urinary tract infection, an intra-abdominalinfection, or a skin infection.

In one aspect, provided herein are compounds of Formula I or Formula Ia,or pharmaceutically acceptable salts, polymorphs, solvates, tautomers,metabolites, or N-oxides thereof:

wherein:

-   -   M is a bond, —O—, —S—, —S(O)—, SO₂—, or —N(R⁴)—;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;        -   provided that            -   when n is 0, then M is a bond;    -   p is 0, 1, 2, or 3;    -   X¹ and X² are independently selected from —OH, —OR⁸, or F;    -   Z is >C═O, >C═S, or >SO₂;    -   ArA is an optionally substituted aromatic or heteroaromatic ring        system;    -   Each Y is selected from the group consisting of        -   fluoro, chloro, bromo, —CN, optionally substituted C₁-C₆            alkyl, optionally substituted C₃-C₆ cycloalkyl, optionally            substituted heterocycle, optionally substituted aryl,            optionally substituted heteroaryl, ═O, —OH, —OR¹⁰, —SR¹⁰,            —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —O(CR⁶R⁷)_(v)NR⁴R⁵, —S(O)_(0,1,2)(CR⁶R⁷)_(v)NR⁴R⁵,            —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(v)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)OR¹⁰,            —NR⁴(CR⁶R⁷)_(v)S(O)_(0,1,2)R¹⁰, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(═NR⁵)R⁶,            —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —S(O)_(0,1,2)—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶,            —NR⁴SO₂R⁶, —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O)NR⁴R⁵,            —(CR⁶R⁷)_(v)C(O)NR⁴R⁵, —SO₂NR⁴R⁵, -Heteroaryl-NR⁴R⁵,            -Heterocyclyl-NR⁴R⁵, -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —N(R⁴)—Heteroaryl-NR⁴R⁵,            —N(R⁴)—Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl, —(CR⁶R⁷)_(v)Heterocyclyl,            —O-Heteroaryl, —O-Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)Heteroaryl,            —NR⁴(CR⁶R⁷)_(v)Heterocyclyl, —O(CR⁶R⁷)_(v)Heteroaryl,            —O(CR⁶R⁷)_(v)Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)NR⁵-Heteroaryl,            —NR⁴(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,            —O(CR⁶R⁷)_(v)NR⁵-Heteroaryl, —O(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,            —O(CR⁶R⁷)_(v)O-Heterocyclyl, —NR⁴R⁵R⁹⁺Q⁻,            —(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻,            —NR⁴R⁹⁺(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻ ₂, —(CR⁶R⁷)_(v)(T)⁺Q⁻, and            —O(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻;        -   wherein:            -   T is pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl;            -   Q is a pharmaceutically acceptable counterion; and            -   v is 1-4;        -   or two Ys taken together with the carbon atoms to which they            are attached form an optionally substituted carbocycle or an            optionally substituted heterocycle;    -   R^(a), R^(b), and R^(c) are independently selected from the        group consisting of hydrogen, fluoro, chloro, bromo, optionally        substituted C₁-C₆ alkyl, optionally substituted C₃-C₆        cycloalkyl, optionally substituted heterocyclyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —OR¹⁰,        —NR⁴R⁵, and —SR¹⁰;    -   R¹ and R² are independently selected from the group consisting        of hydrogen, fluoro, chloro, bromo, optionally substituted C₁-C₆        alkyl, optionally substituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰,        —SR¹⁰, and —NR⁴R⁵,        -   or R¹ and R² taken together form an oxo, oxime, or an            optionally substituted carbocycle or optionally substituted            heterocycle with the carbon to which they are attached;    -   R³ is hydrogen, optionally substituted C₁-C₆ alkyl, or a        pharmaceutically acceptable prodrug;    -   R^(d), R⁴, and R⁵ are independently selected from the group        consisting of hydrogen, —OH, —CN, optionally substituted C₁-C₆        alkyl, optionally substituted alkoxyalkyl, optionally        substituted hydroxyalkyl, optionally substituted aminoalkyl,        optionally substituted cycloalkyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkylalkyl,        optionally substituted heterocyclylalkyl, optionally substituted        aralkyl, optionally substituted heteroaralkyl,        (poly-ethylene-glycol)-ethyl, and an optionally substituted        saccharide; or R⁴ and R⁵ taken together form an optionally        substituted heterocycle with the nitrogen to which they are        attached;    -   R⁶ and R⁷ are independently selected from the group consisting        of hydrogen, fluoro, chloro, bromo, optionally substituted C₁-C₆        alkyl, optionally substituted alkoxyalkyl, optionally        substituted hydroxyalkyl, optionally substituted C₃-C₆        cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R¹, —C(O)NR⁴R⁵,        —NR⁴SO₂R⁵, optionally substituted heterocyclyl, optionally        substituted aryl, and optionally substituted heteroaryl;        -   or R⁶ and R⁷ taken together form an oxo, oxime, or an            optionally substituted carbocycle or an optionally            substituted heterocycle with the carbon to which they are            attached;    -   R⁸ is optionally substituted C₁-C₆ alkyl, optionally substituted        C₃-C₆ cycloalkyl, or a pharmaceutically acceptable boronate        ester group;    -   R⁹ is optionally substituted C₁-C₆ alkyl;    -   R¹⁰ is optionally substituted C₁-C₆ alkyl or optionally        substituted C₃-C₆ cycloalkyl.

In another aspect, provided herein are a compound of Formula (I) orFormula (Ia), a pharmaceutically acceptable salt, polymorph, solvate,prodrug, N-oxide, or isomer thereof:

wherein:

-   -   M is a bond, —O—, —S—, —S(O)—, SO₂—, or —N(R⁴)—;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;        -   provided that        -   when n is 0, then M is a bond;    -   p is 2, 3, 4, or 5;    -   X¹ and X² are independently selected from —OH, —OR⁸, or F;    -   Z is >C═O, >C═S, or >SO₂;    -   ArA is an aromatic or heteroaromatic ring system optionally        substituted with one or more substituents from the group        consisting of fluoro, chloro, bromo, —CN, optionally substituted        C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl, optionally        substituted heterocycle, optionally substituted aryl, optionally        substituted heteroaryl, —OH, —OR¹⁰, and —SR¹⁰;    -   each Y is selected from the group consisting of,        -   —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —O(CR⁶R⁷)_(v)NR⁴R⁵, —S(O)_(0,1,2)(CR⁶R⁷)_(v)NR⁴R⁵,            —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(v)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)OR¹⁰,            —NR⁴(CR⁶R⁷)_(v)S(O)_(0,1,2)R¹⁰, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(═NR⁵)R⁶,            —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —S(O)_(0,1,2)—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶,            —NR⁴SO₂R⁶, —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O)NR⁴R⁵,            —(CR⁶R⁷)_(v)C(O)NR⁴R⁵, —SO₂NR⁴R⁵, -Heteroaryl-NR⁴R⁵,            -Heterocyclyl-NR⁴R⁵, -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —N(R⁴)—Heteroaryl-NR⁴R⁵,            —N(R⁴)—Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl, —(CR⁶R⁷)_(v)Heterocyclyl,            —O-Heteroaryl, —O-Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)Heteroaryl,            —NR⁴(CR⁶R⁷)_(v)Heterocyclyl, —O(CR⁶R⁷)_(v)Heteroaryl,            —O(CR⁶R⁷)_(v)Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)NR⁵-Heteroaryl,            —NR⁴(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,            —O(CR⁶R⁷)_(v)NR⁵-Heteroaryl, —O(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,            —O(CR⁶R⁷)_(v)O-Heterocyclyl, —NR⁴R⁵R⁹⁺Q⁻,            —(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻,            —NR⁴R⁹⁺(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻ ₂, —(CR⁶R⁷)_(v)(T)⁺Q⁻, and            —O(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻;        -   wherein:            -   T is pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl;            -   Q is a pharmaceutically acceptable counterion; and            -   v is 1-4;        -   or two Ys taken together with the carbon atoms to which they            are attached form an optionally substituted carbocycle or an            optionally substituted heterocycle;    -   R^(a), R^(b), and R^(c) are independently selected from the        group consisting of hydrogen, fluoro, chloro, bromo, optionally        substituted C₁-C₆ alkyl, optionally substituted C₃-C₆        cycloalkyl, optionally substituted heterocyclyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —OR¹⁰,        —NR⁴R⁵, and —SR¹⁰;    -   R¹ and R² are independently selected from the group consisting        of hydrogen, fluoro, chloro, bromo, optionally substituted C₁-C₆        alkyl, optionally substituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰,        —SR¹⁰, and —NR⁴R⁵,        -   or R¹ and R² taken together form an oxo, oxime, or an            optionally substituted carbocycle or optionally substituted            heterocycle with the carbon to which they are attached;    -   R³ is hydrogen, optionally substituted C₁-C₆ alkyl, or a        pharmaceutically acceptable prodrug;    -   R^(d), R⁴ and R⁵ are independently selected from the group        consisting of hydrogen, —OH, —CN, optionally substituted C₁-C₆        alkyl, optionally substituted alkoxyalkyl, optionally        substituted hydroxyalkyl, optionally substituted aminoalkyl,        optionally substituted cycloalkyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkylalkyl,        optionally substituted heterocyclylalkyl, optionally substituted        aralkyl, optionally substituted heteroaralkyl,        (poly-ethylene-glycol)-ethyl, and an optionally substituted        saccharide; or R⁴ and R⁵ taken together form an optionally        substituted heterocycle with the nitrogen to which they are        attached;    -   R⁶ and R⁷ are independently selected from the group consisting        of hydrogen, fluoro, chloro, bromo, optionally substituted C₁-C₆        alkyl, optionally substituted alkoxyalkyl, optionally        substituted hydroxyalkyl, optionally substituted C₃-C₆        cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵, —C(O)NR⁴R⁵,        —NR⁴SO₂R⁵, optionally substituted heterocyclyl, optionally        substituted aryl, and optionally substituted heteroaryl;        -   or R⁶ and R⁷ taken together form an oxo, oxime, or an            optionally substituted carbocycle or an optionally            substituted heterocycle with the carbon to which they are            attached;    -   R⁸ is optionally substituted C₁-C₆ alkyl, optionally substituted        C₃-C₆ cycloalkyl, or a pharmaceutically acceptable boronate        ester group;    -   R⁹ is optionally substituted C₁-C₆ alkyl;    -   R¹⁰ is optionally substituted C₁-C₆ alkyl or optionally        substituted C₃-C₆ cycloalkyl.

In some embodiments of a compound of Formula I or Formula Ia, R^(a),R^(b), and R^(c) are independently selected from the group consisting ofhydrogen, fluoro, chloro, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —NR⁴R⁵, and —SR¹⁰. In certainembodiments, R^(a), R^(b), and R^(c) are independently hydrogen, fluoro,or chloro. In preferred embodiments, R^(a), R^(b), and R^(c) arehydrogen.

In some embodiments of a compound of Formula I or Formula Ia, R³ ishydrogen, methyl, ethyl, propyl, butyl, or isopropyl. In preferredembodiments, R³ is hydrogen.

In some embodiments of a compound of Formula I or Formula Ia, X¹ and X²are —OH.

In some embodiments of a compound of Formula I or Formula Ia, R^(d) ishydrogen or C₁-C₄-alkyl. In some embodiments, R^(d) is methyl. Inpreferred embodiments, R^(d) is hydrogen.

In some embodiments of a compound of Formula I or Formula a, Z is Zis >C═O or >SO₂. In preferred embodiments, Z is >C═O.

In some embodiments of a compound of Formula I or Formula Ia, ArA isselected from the group consisting of benzene, naphthalene, pyridine,pyrimidine pyrazine, pyridazine, triazine, thiophene, furan, pyrrole,pyrazole, triazole, imidazole, thiazole, isothiazole, oxazole,isoxazole. indole, indazole, azaindole, azaindazole, isoindole,indolizine, imidazopyridine, pyrazolo-pyridine, thiazolo-pyridinepyrrolo-pyrimidine, thieno-pyrazole, benzimidazole, benzothiazole,benzoxazole, benzofuran, benzisoxazole, benzisothiazole, quinoline,isoquinoline, quinoxaline, quinazoline, cinnoline, benzotriazinenapthyridine, pyrido-pyrimidine, pyrido-pyrazine, pyridopyridazine,isoxazolo-pyridine, and oxazolo-pyridine. In certain embodiments ArA isselected from the group consisting of benzene, pyridine, pyrimidine,thiophene, thiazole, triazole, indole, benzimidazole, azaindole,thienopyrazole, quinoline, quinazoline, and quinoxaline. In preferredembodiments, ArA is benzene, thiophene, pyridine, aza-indole, orquinoxaline.

In some embodiments of a compound of Formula I or Formula Ia, at leastone Y is selected from the group consisting fluoro, chloro, —CN,optionally substituted C₁-C₆ alkyl, —OH, —OR¹⁰, —NR⁴R⁵,—(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵,—N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,—C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(═NR⁵)R⁶,—(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵,—C(═NR⁴)NR⁴C(O)R⁶, —NR⁴SO₂R⁶, —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O)NR⁴R⁵,—(CR⁶R⁷)_(v)C(O)NR⁴R⁵, -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,-Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,—N(R⁴)—Heteroaryl-NR⁴R⁵, —N(R⁴)—Heterocycyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl,—(CR⁶R⁷)_(v)Heterocyclyl, —O-Heteroaryl, —O-Heterocyclyl,—NR⁴(CR⁶R⁷)_(v)Heteroaryl, —NR⁴(CR⁶R⁷)_(v)Heterocyclyl,—O(CR⁶R⁷)_(v)Heteroaryl, —O(CR⁶R⁷)_(v)Heterocycyl, and—O(CR⁶R⁷)_(v)O-Heterocyclyl. In certain embodiments, at least one Y isselected from the group consisting fluoro, chloro, —CN, optionallysubstituted C₁-C₆ alkyl, —OH, —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵,—C(═NR⁴)NR⁴C(O)R⁶, —NR⁴C(O)R⁶, —(CR⁶R⁷)_(v)C(O)NR⁴R⁵,-Heterocyclyl-NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,—N(R⁴)—Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl,and —NR⁴(CR⁶R⁷)_(v)Heterocyclyl. In further embodiments, at least one Yis selected from the group consisting of -Heteroaryl-NR⁴R⁵,-Heterocyclyl-NR⁴R⁵, -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,-Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —N(R⁴)—Heteroaryl-NR⁴R⁵,—N(R⁴)—Heterocyclyl-NR⁴R⁵, -Heteroaryl-C(═NR⁵)NR⁴R⁵,-Heterocyclyl-C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, and—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵. In specific embodiments, atleast one Y is 2-(NR₄R₅)-pyridyl, 2-(NR₄R₅)-pyrimidinyl,2-(NR₄R₅)-thiazolyl, 2-(NR₄R₅)-imidazolyl, 3-(NR₄R₅)-pyrazolyl,3-(R₄R₅N)-isothiazolyl, 2-(R₄R₅N)-oxazolyl, piperidine, pyrrolidine,4-amino-piperidinyl, 3-amino-pyrrolidinyl, piperazine, or4-carboximidoyl-piperazinyl. In preferred embodiments, at least one Y isselected from the group consisting of —NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵,—C(═NR⁴)NR⁴R⁵, —N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)OR¹⁰, —(CR⁶R⁷)_(v)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,NR⁵C(═NR⁵)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁵C(O)CR⁶(NR⁴R⁵)(CR⁶R⁷)_(v)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶,—NR⁴(CR⁶R⁷)_(v)Heteroaryl, and —O(CR⁶R⁷)_(v)NR⁴R⁵.

In certain embodiments, two Y groups taken together with the carbonatoms to which they are attached form an optionally substitutedcarbocycle or an optionally substituted heterocycle. In someembodiments, the carbocycle or heterocycle is optionally substitutedwith one to three substituents selected from the group consisting offluoro, chloro, bromo, —CN, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₆ cycloalkyl, optionally substitutedheterocycle, optionally substituted aryl, optionally substitutedheteroaryl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵,—C(═NR⁴)NR⁴R⁵, -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl, and —(CR⁶R⁷)_(v)Heterocyclyl. In certainembodiments, the two Y groups, together with the atoms to which they areattached form a pyrrolidine ring.

In some embodiments, p is 0, 1, 2, or 3. In certain embodiments, p is 1or 2. In some embodiments, p is 2. In other embodiments, p is 1.

In some embodiments of a compound of Formula I or Formula Ia, R⁴ and R⁵are independently selected from the group consisting of hydrogen, —OHoptionally substituted C₁-C₆ alkyl, optionally substituted alkoxyalkyl,optionally substituted hydroxyalkyl, and optionally substitutedheterocyclyl. In preferred embodiments, R⁴ and R⁵ are independentlyhydrogen or optionally substituted C₁-C₆ alkyl.

In some embodiments of a compound of Formula I or Formula Ia, R⁶ and R⁷are independently selected from the group consisting of hydrogen,optionally substituted C₁-C₆ alkyl, —OH, —NR⁴R⁵, and optionallysubstituted heterocyclyl, or R⁶ and R⁷ taken together form an optionallysubstituted heterocycle with the carbon to which they are attached. Inpreferred embodiments, R⁶ and R⁷ are independently hydrogen, fluoro, oroptionally substituted C₁-C₆ alkyl.

In some embodiments of the compounds of Formula I or Formula Ia, R^(a),R^(b), R^(c), R³ are hydrogen; X¹ and X² are —OH; Z is >C═O; n is 0; mis 0 or 1; R¹ and R², when present are hydrogen; ArA is benzene orpyridine; p is 2; and at least one Y is —(CH₂)_(v)NR⁴R⁵; v is 1 or 2;and R⁴ and R are H or C₁-C₆ alkyl. In some embodiments of the compoundsof Formula I or Formula Ia, R^(a), R^(b), R^(c), R³ are hydrogen; X¹ andX² are —OH; Z is >C═O; n is 0; m is 0 or 1; R¹ and R², when present arehydrogen; ArA is benzene or pyridine; p is 2; and at least two Y groupsare —(CH₂)_(v)NR⁴R⁵; v is 1 or 2; and R⁴ and R⁵ are H or C₁-C₆ alkyl. Insome embodiments of the compounds of Formula I or Formula Ia, R^(a),R^(b), R^(c), R³ are hydrogen; X¹ and X² are —OH Z is >C═O; n is 0; m is0; ArA is benzene or pyridine; p is 2; and two Y groups are—(CH₂)_(v)NR⁴R⁵; v is 1 or 2; and R⁴ and R⁵ are H or C₁-C₆ alkyl. Insome embodiments of the compounds of Formula I or Formula Ia, R^(a),R^(b), R^(c), R³ are hydrogen; X¹ and X² are —OH; Z is >C═O; n is 0; mis 0; ArA is benzene or pyridine; p is 2; and two Y groups are—(CH₂)_(v)NR⁴R⁵; v is 1; and R⁴ and R⁵ are H or C₁-C₆ alkyl. In someembodiments of the compounds of Formula I or Formula Ia, R^(a), R^(b),R^(c), R³ are hydrogen; X¹ and X² are —OH; Z is >C═O; n is 0; m is 0;ArA is benzene or pyridine; p is 2; and two Y groups are—(CH₂)_(v)NR⁴R⁵; v is 1; and R⁴ and R⁵ are H In some embodiments of thecompounds of Formula I or Formula Ia, R^(a), R^(b), R^(c), R³ arehydrogen; X¹ and X² are —OH; Z is >C═O; n is 0; m is 0; ArA is benzene;p is 2; and two Y groups are —(CH₂)_(v)NR⁴R⁵; v is 1; and R⁴ and R⁵ areH.

In some embodiments of the compounds of Formula I or Formula Ia, R^(a),R^(b), R^(c), R³ are hydrogen; X¹ and X² are —OH; Z is >C═O; n is 0; mis 0 or 1; R¹ and R², when present are hydrogen; ArA is benzene orpyridine; p is 2; and two Y groups, together with the atoms to whichthey are attached form an optionally substituted carbocycle or anoptionally substituted heterocycle. In some embodiments, two Y groups,together with the atoms to which they are attached form an optionallysubstituted pyrroline or tetrahydropyridine ring. In some embodiments,two Y groups together with the atoms to which they are attached form anoptionally substituted pyrroline ring. In some embodiments, thecarbocycle or heterocycle is substituted with one to three substituentsselected from the group consisting of fluoro, chloro, bromo, —CN,optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted heterocycle, optionally substitutedaryl, optionally substituted heteroaryl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵,—(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵, -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl, and —(CR⁶R⁷)_(v)Heterocycyl.

In some embodiments of the compounds of Formula I or Formula a, M is abond; m and n are 0; p is 0, 1, 2, or 3; X¹ and X² are independentlyselected from —OH, —OR⁸, or F; R^(a), R^(b), R^(c), R³ are hydrogen; ArAis an aromatic or heteroaromatic group optionally substituted with oneor more substituents from the group consisting of fluoro, chloro, bromo,—CN, optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted heterocycle, optionally substitutedaryl, optionally substituted heteroaryl, —OH, —OR¹⁰, and —SR¹⁰. In someembodiments, ArA is selected from the group consisting of pyrimidine,pyrazine, pyridazine, triazine, thiophene, furan, pyrrole, pyrazole,triazole, imidazole, isothiazole, oxazole, isoxazole, indole, indazole,azaindole, azaindazole, indolizine, imidazopyridine, pyrazolo-pyridine,thiazolo-pyridine pyrrolo-pyrimidine, thieno-pyrazole, benzimidazole,benzothiazole, benzoxazole, benzofuran, benzisoxazole, benzisothiazole,quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline,benzotriazine napthyridine, pyrido-pyrimidine, pyrido-pyrazine,pyridopyridazine, isoxazolo-pyridine, and oxazolo-pyridine. In someembodiments, ArA is a bicyclic aromatic group, for example, ArA isselected from the group consisting of indole, indazole, azaindole,azaindazole, indolizine, imidazopyridine, pyrazolo-pyridine,thiazolo-pyridine pyrrolo-pyrimidine, thieno-pyrazole, benzimidazole,benzothiazole, benzoxazole, benzofuran, benzisoxazole, benzisothiazole,quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline,benzotriazine napthyridine, pyrido-pyrimidine, pyrido-pyrazine,pyridopyridazine, isoxazolo-pyridine, and oxazolo-pyridine. In someembodiments, ArA is selected from the group consisting of pyrimidine,thiophene, oxazole, triazole, indole, benzimidazole, azaindole,thienopyrazole, quinoline, quinazoline, and quinoxaline.

In some embodiments of the compounds of Formula I or Formula Ia, M is abond; m is 0; n is 1; p is 0, 1, 2, or 3; X¹ and X² are independentlyselected from —OH, —OR⁸, or F; R^(a), R^(b), R^(c), R³ are hydrogen; ArAis an aromatic or heteroaromatic group optionally substituted with oneor more substituents from the group consisting of fluoro, chloro, bromo,—CN, optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted heterocycle, optionally substitutedaryl, optionally substituted heteroaryl, —OH, —OR¹⁰, and —SR¹⁰. In someembodiments, ArA is selected from the group consisting of pyrimidine,pyrazine, pyridazine, triazine, thiophene, furan, pyrrole, pyrazole,triazole, imidazole, isothiazole, oxazole, isoxazole, indole, indazole,azaindole, azaindazole, indolizine, imidazopyridine, pyrazolo-pyridine,thiazolo-pyridine pyrrolo-pyrimidine, thieno-pyrazole, benzimidazole,benzothiazole, benzoxazole, benzofuran, benzisoxazole, benzisothiazole,quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline,benzotriazine napthyridine, pyrido-pyrimidine, pyrido-pyrazine,pyridopyridazine, isoxazolo-pyridine, and oxazolo-pyridine. In preferredembodiments, ArA is a bicyclic aromatic group, for example, ArA isselected from the group consisting of indole, indazole, azaindole,azaindazole, indolizine, imidazopyridine, pyrazolo-pyridine,thiazolo-pyridine pyrrolo-pyrimidine, thieno-pyrazole, benzimidazole,benzothiazole, benzoxazole, benzofuran, benzisoxazole, benzisothiazole,quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline,benzotriazine napthyridine, pyrido-pyrimidine, pyrido-pyrazine,pyridopyridazine, isoxazolo-pyridine, and oxazolo-pyridine. In someembodiments, ArA is indole, indazole, azaindole, azaindazole, indolizineor, benzimidazole. In certain embodiments, ArA is selected from thegroup consisting of pyrimidine, thiophene, oxazole, triazole, indole,benzimidazole, azaindole, thienopyrazole, quinoline, quinazoline, andquinoxaline.

In another aspect, provided herein are compounds of Formula I or FormulaIa, or pharmaceutically acceptable salts, polymorphs, solvates,tautomers, metabolites, or N-oxides thereof, wherein:

-   -   M is a bond;    -   m is 0;    -   n is 0, 1 or 2;        -   provided that            -   when n is 0, then M is a bond;    -   p is 0, 1, 2, or 3;    -   X¹ and X² are independently selected from —OH, —OR⁸, or F;    -   Z is >C═O, >C═S, or >SO₂;    -   ArA is aromatic or heteroaromatic ring system optionally        substituted with a substituent selected from the group        consisting of fluoro, chloro, bromo, —CN, optionally substituted        C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl, optionally        substituted heterocycle, optionally substituted aryl, optionally        substituted heteroaryl, ═O, —OH, —OR¹⁰, and —SR¹⁰;    -   Each Y is selected from the group consisting of        -   —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —O(CR⁶R⁷)_(v)NR⁴R⁵, —S(O)_(0,1,2)(CR⁶R⁷)_(v)NR⁴R⁵,            —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(v)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)OR¹⁰,            —NR⁴(CR⁶R⁷)_(v)S(O)_(0,1,2)R¹⁰, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(═NR⁵)R⁶,            —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —S(O)_(0,1,2)—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶,            —NR⁴SO₂R⁶, —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O)NR⁴R⁵,            —(CR⁶R⁷)_(v)C(O)NR⁴R⁵, —SO₂NR⁴R⁵, -Heteroaryl-NR⁴R⁵,            -Heterocyclyl-NR⁴R⁵, -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —N(R⁴)—Heteroaryl-NR⁴R⁵,            —N(R⁴)—Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl, —(CR⁶R⁷)_(v)Heterocyclyl,            —O-Heteroaryl, —O-Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)Heteroaryl,            —NR⁴(CR⁶R⁷)_(v)Heterocyclyl, —O(CR⁶R⁷)_(v)Heteroaryl,            —O(CR⁶R⁷)_(v)Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)NR⁵-Heteroaryl,            —NR⁴(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,            —O(CR⁶R⁷)_(v)NR⁵-Heteroaryl, —O(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,            —O(CR⁶R⁷)_(v)O-Heterocyclyl, —NR⁴R⁵R⁹⁺Q⁻,            —(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻,            —NR⁴R⁹⁺(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻ ₂, —(CR⁶R⁷)_(v)(T)⁺Q⁻, and            —O(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q;        -   wherein:            -   T is pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl;            -   Q is a pharmaceutically acceptable counterion; and            -   v is 1-4;        -   or two Ys taken together with the carbon atoms to which they            are attached form an optionally substituted carbocycle or an            optionally substituted heterocycle;    -   R^(a), R^(b), and R^(c) are independently selected from the        group consisting of hydrogen, fluoro, chloro, bromo, optionally        substituted C₁-C₆ alkyl, optionally substituted C₃-C₆        cycloalkyl, optionally substituted heterocyclyl, optionally        substituted aryl, optionally substituted heteroaryl, —OH, —OR¹⁰,        —NR⁴R⁵, and —SR¹⁰.    -   R¹ and R² are independently selected from the group consisting        of fluoro, chloro, bromo, optionally substituted C₁-C₆ alkyl,        optionally substituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, and        —NR⁴R⁵,        -   or R¹ and R² taken together form an oxo, oxime, or an            optionally substituted carbocycle or optionally substituted            heterocycle with the carbon to which they are attached;    -   R³ is hydrogen, optionally substituted C₁-C₆ alkyl, or a        pharmaceutically acceptable prodrug;    -   R^(d), R⁴, and R⁵ are independently selected from the group        consisting of hydrogen, —OH, —CN, optionally substituted C₁-C₆        alkyl, optionally substituted alkoxyalkyl, optionally        substituted hydroxyalkyl, optionally substituted aminoalkyl,        optionally substituted cycloalkyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkylalkyl,        optionally substituted heterocyclylalkyl, optionally substituted        aralkyl, optionally substituted heteroaralkyl,        (poly-ethylene-glycol)-ethyl, and an optionally substituted        saccharide; or R⁴ and R⁵ taken together form an optionally        substituted heterocycle with the nitrogen to which they are        attached;    -   R⁶ and R⁷ are independently selected from the group consisting        of hydrogen, fluoro, chloro, bromo, optionally substituted C₁-C₆        alkyl, optionally substituted alkoxyalkyl, optionally        substituted hydroxyalkyl, optionally substituted C₃-C₆        cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵, —C(O)NR⁴R⁵,        —NR⁴SO₂R⁵, optionally substituted heterocyclyl, optionally        substituted aryl, and optionally substituted heteroaryl;        -   or R⁶ and R⁷ taken together form an oxo, oxime, or an            optionally substituted carbocycle or an optionally            substituted heterocycle with the carbon to which they are            attached;    -   R⁸ is optionally substituted C₁-C₆ alkyl, optionally substituted        C₃-C₆ cycloalkyl, or a pharmaceutically acceptable boronate        ester group;    -   R⁹ is optionally substituted C₁-C₆ alkyl;    -   R¹⁰ is optionally substituted C₁-C₆ alkyl or optionally        substituted C₃-C₆ cycloalkyl.        In some embodiments, R⁶ and R⁷ are independently selected from        the group consisting of fluoro, chloro, bromo, optionally        substituted C₁-C₆ alkyl, optionally substituted alkoxyalkyl,        optionally substituted hydroxyalkyl, optionally substituted        C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵,        —C(O)NR⁴R⁵, —NR⁴SO₂R⁵, optionally substituted heterocyclyl,        optionally substituted aryl, and optionally substituted        heteroaryl; or R⁶ and R⁷ taken together form an optionally        substituted carbocycle or an optionally substituted heterocycle        with the carbon to which they are attached. In some embodiments,        R⁶ and R⁷ are independently selected from the group consisting        of fluoro, chloro, bromo, optionally substituted C₁-C₆ alkyl,        optionally substituted alkoxyalkyl, optionally substituted        hydroxyalkyl, optionally substituted C₃-C₆ cycloalkyl, —OH,        —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵, —C(O)NR⁴R⁵, and —NR⁴SO₂R⁵. In        some embodiments, v is 1; and R⁶ and R⁷ are fluoro. In some        embodiments, v is 1; and R⁶ and R⁷ together with the carbon to        which they are attached form a carbocycle such as cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl        group. In some embodiments, v is 1; and R⁶ and R⁷ together with        the carbon to which they are attached form a heterocycle such as        an aziridine, azetidine, pyrrolidine, or piperidine, for        example. In some embodiments, ArA is phenyl or pyridine. In some        embodiments, R¹ and R² are independently selected from the group        consisting of fluoro, chloro, bromo. In certain embodiments, R¹        and R² taken together form an optionally substituted carbocycle        or optionally substituted heterocycle with the carbon to which        they are attached.

In some embodiments of the compound of Formula 1 or Formula 1a, p is 1,2 or 3; and at least one Y is selected from the group consisting of—O(CR⁶R⁷)_(v)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, and —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵.

In some embodiments of the compound of Formula 1 or Formula 1a, p is 0;and ArA is aryl or heteroaryl substituted with a heteroaryl group. Insome embodiments, p is 0; and ArA is selected from the group consistingof benzene, naphthalene, pyridine, pyrimidine pyrazine, pyridazine,triazine, thiophene, furan, pyrrole, pyrazole, triazole, imidazole,thiazole, isothiazole, oxazole, isoxazole, indole, indazole, azaindole,azaindazole, indolizine, imidazopyridine, pyrazolo-pyridine,thiazolo-pyridine pyrrolo-pyrimidine, thieno-pyrazole, benzimidazole,benzothiazole, benzoxazole, benzofuran, benzisoxazole, benzisothiazole,quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline,benzotriazine napthyridine, pyrido-pyrimidine, pyrido-pyrazine,pyridopyridazine, isoxazolo-pyridine, and oxazolo-pyridine; wherein ArAis substituted with a heteroaryl group. In some embodiments, p is 0 andArA is substituted with a heteroaryl group selected from azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). In some embodiments, p is 0and ArA is benzene, pyridine, or pyrimidine substituted with aheteroaryl group selected from imidazolyl, pyridinyl, pyrimidinyl,pyridazinyl, and triazolyl.

Preparation of Compounds

Described herein are compounds of Formula I or Formula Ia that inhibitthe activity of beta-lactamases, and processes for their preparation.Also described herein are pharmaceutically acceptable salts,pharmaceutically acceptable solvates, pharmaceutically activemetabolites, and pharmaceutically acceptable prodrugs of such compounds.Pharmaceutical compositions comprising at least one such compound or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,pharmaceutically active metabolite or pharmaceutically acceptableprodrug of such compound, and a pharmaceutically acceptable excipientare also provided.

Compounds of Formula I or Formula Ia may be synthesized using standardsynthetic reactions known to those of skill in the art or using methodsknown in the art. The reactions can be employed in a linear sequence toprovide the compounds or they may be used to synthesize fragments whichare subsequently joined by the methods known in the art.

The starting material used for the synthesis of the compounds describedherein may be synthesized or can be obtained from commercial sources,such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.),Bachem (Torrance, Calif.), or Sigma Chemical Co. (St. Louis, Mo.). Thecompounds described herein, and other related compounds having differentsubstituents can be synthesized using techniques and materials known tothose of skill in the art, such as described, for example, in March,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000,2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd)Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); andLarock's Comprehensive Organic Transformations (VCHPublishers Inc.,1989). (all of which are incorporated by reference in their entirety).Other methods for the synthesis of compounds described herein may befound in International Patent Publication No. WO 01/01982901, Arnold etal. Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170;Burchat et al. Bioorganic & Medicinal Chemistry Letters 12 (2002)1687-1690. General methods for the preparation of compound as disclosedherein may be derived from known reactions in the field, and thereactions may be modified by the use of appropriate reagents andconditions, as would be recognized by the skilled person, for theintroduction of the various moieties found in the formulae as providedherein.

The products of the reactions may be isolated and purified, if desired,using conventional techniques, including, but not limited to,filtration, distillation, crystallization, chromatography and the like.Such materials may be characterized using conventional means, includingphysical constants and spectral data.

Compounds described herein may be prepared as a single isomer or amixture of isomers.

Further Forms of Compounds Disclosed Herein

Isomers

In some embodiments, due to the oxophilic nature of the boron atom, thecompounds described herein may convert to or exist in equilibrium withalternate forms, particularly in milieu that contain water (aqueoussolution, plasma, etc.). Accordingly, the compounds described herein mayexist in an equilibrium between the “closed” cyclic form shown inFormula I and the “open” acyclic form shown in Figure Ia. In additionthe compounds described herein may associate into intramolecular dimers,trimers, and related combinations.

Furthermore, in some embodiments, the compounds described herein existas geometric isomers. In some embodiments, the compounds describedherein possess one or more double bonds. The compounds presented hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the corresponding mixtures thereof. In somesituations, compounds exist as tautomers. The compounds described hereininclude all possible tautomers within the formulas described herein. Insome situations, the compounds described herein possess one or morechiral centers and each center exists in the R configuration, or Sconfiguration. The compounds described herein include alldiastereomeric, enantiomeric, and epimeric forms as well as thecorresponding mixtures thereof. In additional embodiments of thecompounds and methods provided herein, mixtures of enantiomers and/ordiastereoisomers, resulting from a single preparative step, combination,or interconversion are useful for the applications described herein. Insome embodiments, the compounds described herein are prepared as theirindividual stereoisomers by reacting a racemic mixture of the compoundwith an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomers. In some embodiments, dissociablecomplexes are preferred (e.g., crystalline diastereomeric salts). Insome embodiments, the diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and are separated by taking advantage of these dissimilarities. In someembodiments, the diastereomers are separated by chiral chromatography,or preferably, by separation/resolution techniques based upondifferences in solubility. In some embodiments, the optically pureenantiomer is then recovered, along with the resolving agent, by anypractical means that would not result in racemization.

In some embodiments, the compound of Formula I or Formula Ia is thestereoisomer represented by any of the structures shown herein. In someembodiments, the compound of Formula I or Formula Ia is an enantiomer ofthe stereoisomer represented by any of the structures shown herein. Incertain embodiments, the compound of Formula I or Formula Ia is adiastereomer of the stereoisomer represented by any of the structuresshown herein. In some embodiments, the compound of Formula I or FormulaIa is a mixture of enantiomers and/or diastereomers of the stereoisomerrepresented by any of the structures shown herein. In certainembodiments, the compound of Formula I or Formula Ia is a racemate ofthe stereoisomer represented by any of the structures herein.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine andchloride, such as ²H, ³H ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds described herein, and the metabolites,pharmaceutically acceptable salts, esters, prodrugs, solvate, hydratesor derivatives thereof which contain the aforementioned isotopes and/orother isotopes of other atoms are within the scope of this invention.Certain isotopically-labeled compounds, for example those into whichradioactive isotopes such as ³H and ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i. e., ³Hand carbon-14, i. e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution with heavyisotopes such as deuterium, i.e., ²H, produces certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements. In someembodiments, the isotopically labeled compounds, pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate or derivative thereofis prepared by any suitable method.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to formapharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds of the invention, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Examples of pharmaceutically acceptable salts include those saltsprepared by reaction of the compounds described herein with a mineral,organic acid or inorganic base, such salts including, acetate, acrylate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate,camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride,citrate, cyclopentanepropionate, decanoate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylate undeconate and xylenesulfonate.

Further, the compounds described herein can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid and muconic acid. In some embodiments, other acids,such as oxalic, while not in themselves pharmaceutically acceptable, areemployed in the preparation of salts useful as intermediates inobtaining the compounds of the invention and their pharmaceuticallyacceptable acid addition salts.

In some embodiments, those compounds described herein which comprise afree acid group react with a suitable base, such as the hydroxide,carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metalcation, with ammonia, or with a pharmaceutically acceptable organicprimary, secondary, tertiary, or quaternary amine. Representative saltsinclude the alkali or alkaline earth salts, like lithium, sodium,potassium, calcium, and magnesium, and aluminum salts and the like.Illustrative examples of bases include sodium hydroxide, potassiumhydroxide, choline hydroxide, sodium carbonate, N⁺(C₁₋₄ alkyl)₄, and thelike.

Representative organic amines useful for the formation of base additionsalts include ethylamine, diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like. It should be understood thatthe compounds described herein also include the quarternization of anybasic nitrogen-containing groups they contain. It should be understoodthat the compounds described herein also include the quarternization ofany boron-containing groups they contain. Such a quarternization couldresult from the treatment of the Lewis acidic bron with a Lewis base toforma complex or salt. In some embodiments, water or oil-soluble ordispersible products are obtained by such quarternization.

Solvates

In some embodiments, the compounds described herein exist as solvates.The invention provides for methods of treating diseases by administeringsuch solvates. The invention further provides for methods of treatingdiseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein can be conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein can be conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran ormethanol. In addition, the compounds provided herein can exist inunsolvated as well as solvated forms. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thecompounds and methods provided herein.

Polymorphs

In some embodiments, the compounds described herein exist as polymorphs.The invention provides for methods of treating diseases by administeringsuch polymorphs. The invention further provides for methods of treatingdiseases by administering such polymorphs as pharmaceuticalcompositions.

Thus, the compounds described herein include all their crystallineforms, known as polymorphs. Polymorphs include the different crystalpacking arrangements of the same elemental composition of a compound. Incertain instances, polymorphs have different X-ray diffraction patterns,infrared spectra, melting points, density, hardness, crystal shape,optical and electrical properties, stability, and solubility. In certaininstances, various factors such as the recrystallization solvent, rateof crystallization, and storage temperature cause a single crystal formto dominate.

Prodrugs

In some embodiments, the compounds described herein exist in prodrugform. The invention provides for methods of treating diseases byadministering such prodrugs. The invention further provides for methodsof treating diseases by administering such prodrugs as pharmaceuticalcompositions.

Prodrugs are generally drug precursors that, following administration toan individual and subsequent absorption, are converted to an active, ora more active species via some process, such as conversion by ametabolic pathway. Some prodrugs have a chemical group present on theprodrug that renders it less active and/or confers solubility or someother property to the drug. Once the chemical group has been cleavedand/or modified from the prodrug the active drug is generated. Prodrugsare often useful because, in some situations, they are easier toadminister than the parent drug. They are, for instance, bioavailable byoral administration whereas the parent is not. In certain instances, theprodrug also has improved solubility in pharmaceutical compositions overthe parent drug. An example, without limitation, of a prodrug would be acompound as described herein which is administered as an ester (the“prodrug”) to facilitate transmittal across a cell membrane where watersolubility is detrimental to mobility but which then is metabolicallyhydrolyzed to the carboxylic acid, the active entity, once inside thecell where water-solubility is beneficial. A further example of aprodrug might be a short peptide (polyamino acid) bonded to an acidgroup where the peptide is metabolized to reveal the active moiety. (Seefor example Bundgaard, “Design and Application of Prodrugs” in ATextbook of Drug Design and Development, Krosgaard-Larsen and Bundgaard,Ed., 1991, Chapter 5, 113-191, which is incorporated herein byreference).

In some embodiments, prodrugs are designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. The design of prodrugs to date has been toincrease the effective water solubility of the therapeutic compound fortargeting to regions where water is the principal solvent.

Additionally, prodrug derivatives of compounds described herein can beprepared by methods described herein are otherwise known in the art (forfurther details see Saulnier et al., Bioorganic and Medicinal ChemistryLetters, 1994, 4, 1985). By way of example only, appropriate prodrugscan be prepared by reacting a non-derivatized compound with a suitablecarbamylating agent, such as, but not limited to,1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or thelike. Prodrug forms of the herein described compounds, wherein theprodrug is metabolized in vivo to produce a derivative as set forthherein are included within the scope of the claims. Indeed, some of theherein-described compounds are prodrugs for another derivative or activecompound.

In some embodiments, prodrugs include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e. g., two, three orfour) amino acid residues is covalently joined through an amide or esterbond to a free amino, hydroxy or carboxylic acid group of compounds ofthe present invention. The amino acid residues include but are notlimited to the 20 naturally occurring amino acids and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid,cirtulline, homocysteine, homoserine, omithine and methionine sulfone.In other embodiments, prodrugs include compounds wherein a nucleic acidresidue, or an oligonucleotide of two or more (e. g., two, three orfour) nucleic acid residues is covalently joined to a compound of thepresent invention.

Pharmaceutically acceptable prodrugs of the compounds described hereinalso include, but are not limited to, esters, carbonates,thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives,quaternary derivatives of tertiary amines, N-Mannich bases, Schiffbases, amino acid conjugates, phosphate esters, metal salts andsulfonate esters. Compounds having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. In certaininstances, all of these prodrug moieties incorporate groups includingbut not limited to ether, amine and carboxylic acid functionalities.

Hydroxy prodrugs include esters, such as though not limited to,acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters,alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphateesters, sulfonate esters, sulfate esters and disulfide containingesters; ethers, amides, carbamates, hemisuccinates,dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlinedin Advanced Drug Delivery Reviews 1996, 19, 115.

Amine derived prodrugs include, but are not limited to the followinggroups and combinations of groups:

as well as sulfonamides and phosphonamides.

In certain instances, sites on any aromatic ring portions aresusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, can reduce,minimize or eliminate this metabolic pathway.

Metabolites

In some embodiments, compounds of Formula I or Formula Ia aresusceptible to various metabolic reactions. Therefore, in someembodiments, incorporation of appropriate substituents into thestructure will reduce, minimize, or eliminate a metabolic pathway. Inspecific embodiments, the appropriate substituent to decrease oreliminate the susceptibility of an aromatic ring to metabolic reactionsis, by way of example only, a halogen, or an alkyl group.

In additional or further embodiments, the compounds of Formula I orFormula Ia described herein are metabolized upon administration to anorganism in need to produce a metabolite that is then used to produce adesired effect, including a desired therapeutic effect.

Pharmaceutical Compositions/Formulations

In another aspect, provided herein are pharmaceutical compositioncomprising a compound of Formula I or Formula Ia as described herein, ora pharmaceutically acceptable salt, polymorph, solvate, prodrug,N-oxide, or isomer thereof, and a pharmaceutically acceptable excipient.In some embodiments, the pharmaceutical composition further comprises abeta-lactam antibiotic. In certain embodiments, the beta-lactamantibiotic is a penicillin, cephalosporin, carbapenem, monobactam,bridged monobactam, or a combination thereof.

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein can be found, for example,in Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H A and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999),herein incorporated by reference for such disclosure.

Provided herein are pharmaceutical compositions that include a compoundof Formula I or Formula Ia and at least one pharmaceutically acceptableinactive ingredient. In some embodiments, the compounds described hereinare administered as pharmaceutical compositions in which a compound ofFormula I or Formula Ia is mixed with other active ingredients, as incombination therapy. In other embodiments, the pharmaceuticalcompositions include other medicinal or pharmaceutical agents, carriers,adjuvants, preserving, stabilizing, wetting or emulsifying agents,solution promoters, salts for regulating the osmotic pressure, and/orbuffers. In yet other embodiments, the pharmaceutical compositionsinclude other therapeutically valuable substances.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula I or Formula Ia with other chemical components (i.e.pharmaceutically acceptable inactive ingredients), such as carriers,excipients, binders, filling agents, suspending agents, flavoringagents, sweetening agents, disintegrating agents, dispersing agents,surfactants, lubricants, colorants, diluents, solubilizers, moisteningagents, plasticizers, stabilizers, penetration enhancers, wettingagents, anti-foaming agents, antioxidants, preservatives, or one or morecombination thereof. The pharmaceutical composition facilitatesadministration of the compound to an organism. In practicing the methodsof treatment or use provided herein, therapeutically effective amountsof compounds described herein are administered in a pharmaceuticalcomposition to a mammal having a disease, disorder, or condition to betreated. In some embodiments, the mammal is a human. A therapeuticallyeffective amount can vary widely depending on the severity of thedisease, the age and relative health of the subject, the potency of thecompound used and other factors. The compounds can be used singly or incombination with one or more therapeutic agents as components ofmixtures.

The pharmaceutical formulations described herein are administered to asubject by appropriate administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, liquids, gels, syrups,elixirs, slurries, suspensions, self-emulsifying dispersions, solidsolutions, liposomal dispersions, aerosols, solid oral dosage forms,powders, immediate release formulations, controlled releaseformulations, fast melt formulations, tablets, capsules, pills, powders,dragees, effervescent formulations, lyophilized formulations, delayedrelease formulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate andcontrolled release formulations.

Pharmaceutical compositions including a compound of Formula I or FormulaIa are manufactured in a conventional manner, such as, by way of exampleonly, by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

The pharmaceutical compositions will include at least one compound ofFormula I or Formula Ia as an active ingredient in free-acid orfree-base form, or in a pharmaceutically acceptable salt form. Inaddition, the methods and pharmaceutical compositions described hereininclude the use of N-oxides (if appropriate), crystalline forms,amorphous phases, as well as active metabolites of these compoundshaving the same type of activity. In some embodiments, compoundsdescribed herein exist in unsolvated form or in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. The solvated forms of the compounds presented herein are alsoconsidered to be disclosed herein.

Pharmaceutical preparations for oral use are obtained by mixing one ormore solid excipient with one or more of the compounds described herein,optionally grinding the resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include, for example,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents are added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate. In some embodiments, dyestuffs orpigments are added to the tablets or dragee coatings for identificationor to characterize different combinations of active compound doses.

Pharmaceutical preparations that are administered orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules contain the active ingredients in admixture with filler such aslactose, binders such as starches, and/or lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive compounds are dissolved or suspended in suitable liquids, such asfatty oils, liquid paraffin, or liquid polyethylene glycols. In someembodiments, stabilizers are added.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Combination Treatment

The compounds according to Formula I or Formula Ia may be used incombination with one or more antibiotics in the treatment of bacterialinfections. Such antibiotics may be administered, by a route and in anamount commonly used therefore, contemporaneously or sequentially with acompound of Formula I or Ia. When a compound of Formula I or Ia is usedcontemporaneously with one or more antibiotic, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of the present invention is preferred. However, the combinationtherapy may also include therapies in which the compound of Formula I orIA and one or more antibiotic are administered on different overlappingschedules. It is also contemplated that when used in combination withone or more antibiotics, the antibiotics may be used in lower doses thanwhen each is used singly.

Accordingly, the pharmaceutical compositions of the present inventionalso include those that contain one or more antibiotics, in addition toa compound according to Formula I or Formula Ia. In some embodiments, apharmaceutical composition comprising a compound of Formula I or Iafurther comprises a beta-lactam antibiotic. In certain embodiments, thebeta-lactam antibiotic is a penicillin, cephalosporin, carbapenem,monobactam, bridged monobactam, or a combination thereof.

The above combinations include combinations of a compound of Formula Ior Ia not only with one antibiotic, but also with two or moreantibiotics. Likewise, compounds of formula I or Ia, either incombination with an antibiotic or by themselves, may be used incombination with other drugs that are used in the prevention, treatment,control, amelioration, or reduction of risk of bacterial infections orconditions associated with bacterial infections. Such other drugs may beadministered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with a compound of Formula I or Ia.When a compound of Formula I or Ia is used contemporaneously with one ormore other drugs, a pharmaceutical composition containing such otherdrugs in addition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventionalso include those that also contain one or more other activeingredients, in addition to a compound of Formula I or Ia. The weightratio of the compound of Formula I or Ia to the second active ingredientmay be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used.

In some embodiments, the compounds according to Formula I or Formula Iaare used in combination with one or more antibiotics in the treatment ofbacterial infections. In certain embodiments, the bacterial infection isa upper or lower respiratory tract infection, a urinary tract infection,a intra-abdominal infection, or a skin infection. In some embodiments,the one or more antibiotics are selected from β-lactam antibiotics.β-Lactam antibiotics include, but are not limited to, penicillins,penems, carbapenems, cephalosporins, cephamycins, monobactams, orcombinations thereof. Penicillins include, but are not limited to,amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin,benzathine benzylpenicillin, benzathine phenoxymethylpenicillin,benzylpenicillin (G), carbenicillin, carindacillin, clometocillin,cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin,mecillinam, metampicillin, meticillin, mezlocillin, nafcillin,oxacillin, penamecillin, pheneticillin, phenoxymethylpenicillin (V),piperacillin, pivampicillin, pivmecillinam, procaine benzylpenicillin,propicillin, sulbenicillin, talampicillin, temocillin, ticarcillin.Penems include, but are not limited to, faropenem. Carbapenems include,but are not limited to, biapenem, ertapenem, doripenem, imipenem,meropenem, panipenem. Cephalosprins/Cephamycins include, but are notlimited to, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin,cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin,cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone,cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet,cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid,cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin,cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime,cefprozil, cefquinome, cefquinome, cefradine, cefroxadine, cefsulodin,ceftaroline fosamil, ceftazidime, cefteram, ceftezole, ceftibuten,ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone,cefuroxime, cefuzonam, flomoxef, latamoxef, loracarbef. Monobactamsinclude, but are not limited to, aztreonam, carumonam, nocardicin A,tigemonam.

Administration of Pharmaceutical Composition

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In some embodiments, compounds of Formula I or Formula Ia andcompositions thereof are administered in any suitable manner. The mannerof administration can be chosen based on, for example, whether local orsystemic treatment is desired, and on the area to be treated. Forexample, the compositions can be administered orally, parenterally(e.g., intravenous, subcutaneous, intraperitoneal, or intramuscularinjection), by inhalation, extracorporeally, topically (includingtransdermally, ophthalmically, vaginally, rectally, intranasally) or thelike.

Parenteral administration of the composition, if used, is generallycharacterized by injection. Injectables can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solution of suspension in liquid prior to injection, or asemulsions. A more recently revised approach for parenteraladministration involves use of a slow release or sustained releasesystem such that a constant dosage is maintained.

Assays for Antibacterial Activity

Assays for the inhibition of beta-lactamase activity are well known inthe art. For instance, the ability of a compound to inhibitbeta-lactamase activity in a standard enzyme inhibition assay may beused (see, e g, Page, Biochem J, 295:295-304 (1993)). Beta-lactamasesfor use in such assays may be purified from bacterial sources orpreferably, are produced by recombinant DNA techniques, since genes andcDNA clones coding for many beta-lactamases are known (see, e g,Cartwright & Waley, Biochem J 221:505-12 (1984)).

Alternatively, the sensitivity of bacteria known, or engineered, toproduce a beta-lactamase to an inhibitor may be determined. Otherbacterial inhibition assays include agar disk diffusion and agardilution (see, e.g, Traub & Leonhard, Chemotherapy 43 159-67 (1997)).Thus, a beta-lactamase may be inhibited by contacting the beta-lactamaseenzyme with an effective amount of an inventive compound or bycontacting bacteria that produce the beta-lactamase enzymes with aneffective amount of such a compound so that the beta-lactamase in thebacteria is contacted with the inhibitor. The contacting may take placein vitro or in vivo. “Contacting” means that the beta-lactamase and theinhibitor are brought together so that the inhibitor can bind to thebeta-lactamase. Amounts of a compound effective to inhibit abeta-lactamase may be determined empirically, and making suchdeterminations is within the skill in the art. Inhibition includes bothreduction and elimination of beta-lactamase activity.

Methods

The present disclosure also provides methods for inhibiting bacterialgrowth, by, e.g., reducing bacterial resistance to a β-lactamantibiotic, such methods comprising contacting a bacterial cell culture,or a bacterially infected cell culture, tissue, or organism, with abeta-lactamase inhibitor described herein. Preferably, the bacteria tobe inhibited by administration of a beta-lactamase inhibitor of FormulaI or Ia are bacteria that are resistant to beta-lactam antibiotics. Theterm “resistant” is well-understood by those of ordinary skill in theart (see, e g Payne et al., Antimicrobial Agents and Chemotherapy 38767-772 (1994), Hanaki et al., Antimicrobial Agents and Chemotherapy 301120-1126 (1995)).

These methods are useful for inhibiting bacterial growth in a variety ofcontexts. In certain embodiments, a compound of Formula I or Ia isadministered to an experimental cell culture in vitro to prevent thegrowth of beta-lactam resistant bacteria. In certain other embodiments,a compound of Formula I or Ia is administered to a mammal, including ahuman to prevent the growth of beta-lactam resistant bacteria in vivo.The method according to this embodiment comprises administering atherapeutic ally effective amount of a beta-lactamase inhibitor for atherapeutically effective period of time to a mammal, including a human.Preferably, the beta-lactamase inhibitor is administered in the form ofa pharmaceutical composition as described above. In some embodiments, abeta-lactam antibiotic is co-administered with the beta-lactamaseinhibitor as described above.

In another aspect provided herein are methods of treating a bacterialinfection, which method comprises administering to a subject apharmaceutical composition comprising a compound of Formula I or FormulaIa, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient. In some embodiments, the methodsof treating a bacterial infection in a subject comprises administeringto the subject a pharmaceutical composition as described herein,optionally in combination with a beta-lactam antibiotic. In someembodiments, the bacterial infection is an upper or lower respiratorytract infection, a urinary tract infection, an intra-abdominalinfection, or a skin infection.

In some embodiments, the infection that is treated or preventedcomprises a bacteria that includes Pseudomonas aeruginosa, Pseudomonasfluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes,Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia,Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii,Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi,Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri,Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes,Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens,Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteusvulgaris, Providencia alcalifaciens, Providencia rettgeri, Providenciastuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus,Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis,Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis,Bordetella parapertussis, Bordetella bronchiseptica, Haemophilusinfluenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus,Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurellamultocida, Pasteurella haemolytica, Branhamella catarrhalis,Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni,Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrioparahaemolyticus, Legionella pneumophila, Listeria monocytogenes,Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,Gardnerella vaginalis, Bacteroidesfragilis, Bacteroides distasonis,Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroidesovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, Bacteroides splanchnicus, Clostridium difficile,Mycobacterium tuberculosis, Mycobacterium avium, Mycobacteriumintracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcusagalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcusfaecium, Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcushyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcushominis, or Staphylococcus saccharolyticus.

In some embodiments, the infection that is treated or preventedcomprises a bacteria that includes Pseudomonas aeruginosa, Pseudomonasfluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacterfreundii, Salmonella typhimurium, Salmonella typhi, Salmonellaparatyphi, Salmonella enteritidis, Shigella dysenteriae, Shigellaflexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes,Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens,Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersiniaenterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersiniaintermedia, Haemophilus influenzae, Haemophilus parainfluenzae,Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacterpylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli,Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila,Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis,Moraxella, Bacteroidesfragilis, Bacteroides vulgatus, Bacteroidesovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, or Bacteroides splanchnicus.

EXAMPLES List of Abbreviations

As used above, and throughout the description of the invention, thefollowing abbreviations, unless otherwise indicated, shall be understoodto have the following meanings:

ACN acetonitrile

Bn benzyl

BOC or Boc tert-butyl carbamate

BOP benzotriazol-1-yl-oxytris (dimethylamino) phosphonium

t-Bu tert-butyl

Cbz benzyl carbamate

Cy Cyclohexyl

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCC dicyclohexylcarbodiimide

DCM dichloromethane (CH₂CI₂)

DIC 1,3-diisopropylcarbodiimide

DEAD diethyl azodicarboxylate

DIAD diisopropyl azodicarboxylate

DIEA diisopropylethylamine

DMAP 4-(N,N-dimethylamino)pyridine

DMP reagent Dess-Martin Periodinane reagent

DMF dimethylformamide

DMA N,N-Dimethylacetamide

DME 1,2-Dimethoxy-ethane

DMSO dimethylsulfoxide

Dppf 1,1′-Bis(diphenylphosphino)ferrocene

EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl

eq equivalent(s)

Et ethyl

Et₂O diethyl ether

EtOH ethanol

EtOAc ethyl acetate

HOAt 1-hydroxy-7-azabenzotriazole

HOBT 1-hydroxybenztriazole

HOSu N-hydroxysuccinamide

HPLC high performance liquid chromatography

LAH lithium aluminum anhydride

Me methyl

MeI methyliodide

MeOH methanol

MOMCl methoxymethylchloride

MOM methoxymethyl

MS mass spectroscopy

NMP N-methyl-pyrrolidin-2-one

NMR nuclear magnetic resonance

PyBOP benzotriazole-1-yl-oxytris-pyrrolidino-phosphoniumHexafluorophosphate

SPHOS 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl

TBD 1,5,7-triazabicyclo[4.4.0]-dec-5-ene

RP-HPLC reverse phase-high pressure liquid chromatography

TBS tert-butyldimethylsilyl

TBSCl tert-butyldimethylsilyl chloride

TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium

TEOC 2-Trimethylsilylethyl Carbamate

TFA trifluoroacetic acid

Tf₂O triflate anhydride

TMG 1,1,3,3-Tetramethylguanidine

THF tetrahydrofuran

THP tetrahydropyran

TLC thin layer chromatography

XPHOS 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

General Examples for the Preparation of Compounds of the Invention

The starting materials and intermediates for the compounds of thisinvention may be prepared by the application or adaptation of themethods described below, their obvious chemical equivalents, or, forexample, as described in literature such as The Science of Synthesis,Volumes 1-8. Editors E. M. Carreira et al. Thieme publishers(2001-2008). Details of reagent and reaction options are also availableby structure and reaction searches using commercial computer searchengines such as Scifinder (www.cas.org) or Reaxys (www.reaxys.com).

Certain compounds of the invention (I) (SCHEME 1) are prepared from thecorresponding functional-group-protected boronic acid esters (II) bytreatment with a Lewis acid such as BCl₃, in a solvent such asdichloromethane, at a temperature between −78° C. and 0° C. followed byan aqueous quench.

Alternatively, (I) is obtained from (II) by treatment of (II) withaqueous hydrochloric acid (around 3-5 Molar) in dioxane at a temperaturebetween room temperature and 100° C.

The requisite boronic acid esters (II) are obtained (SCHEME 2) bycoupling of amine (III) with (carboxylic or sulphonic) acid (IV). Thistransformation is effected by first activating the acid functionality asan acid chloride, anhydride or reactive ester (Va, Vb or Vc), followedby treatment of the activated substrate with (III) in a solvent such asDMF, DMA, NMP, THF or dichloromethane (or a mixture thereof) at aboutroom temperature, usually in the presence of anon-nucleophilic base suchas 4-methyl-morpholine, triethylamine or diisopropylethylamine.

Formation of the acid chloride (Va) involves treatment of (IV) with achlorinating agent such as thionyl chloride, phosphorous pentachlorideor oxalyl chloride, in a solvent such as dichloromethane, in thepresence of a catalyst such as DMF, at around room temperature. Incertain cases, DMF is also used as a co-solvent. Formation of theanhydride (Vb) (Z is C═O) involves treatment of (IV) with a stericallyhindered acid chloride or chloroformate, such as trimethylacetylchloride or isopropylchloroformate, in an inert solvent such asdichloromethane, in the presence of anon-nucleophilic base, such astriethyl amine or diisopropylamine at room temperature or below.Formation of the activated ester (Vc) involves treatment of (IV) with anactivating reagent system such as EDCI, DCC/HOBt, HATU, BOP reagents orTBTU, in a solvent such as DMF, DMA, NMP or dichloromethane at roomtemperature or below (International Journal of Pharmaceutical SciencesReview and Research (2011), 8(1), 108-119).

The requisite acids (IV) are prepared by a number of different reactionsequences. While there are common themes and strategies among theillustrative examples cited below, the selection of an appropriatereaction sequence (including protecting group requirements) is dictatedby the nature and arrangement of the functionality present in the targetmolecule and, therefore, may involve obvious adaptations of theillustrated methods in order to be applied in a particular case.

In the case where Y₁=an optionally substituted 1,3-diamino-propyl, or1,4 diamino-butyl (SCHEME 3), the requisite acids (IV) are prepared bytreatment of the appropriate benzyloxy-alkyl substituted benzaldehyde orphenyl-ketone (VIa VIb) with t-butylsufimamine (Chemical Reviews,(2010), 110(6), 3600-3740), typically in a solvent such asdichoromethane, ether, benzene or toluene, in the presence of a Lewisacid or desiccant such as MgSO₄, CSO₄, Ti(OEt)₄ or molecular sieves and,in some cases, in a Dean Stark type reactor system. The resultingt-butylsuphinimine (VII) is then condensed with an appropriateorganometallic, such as an olefin substituted alkyl Grignard, in asolvent such as THF, ether, dichloromethane or toluene at a temperaturebetween −60° and 0° C., to provide the sulfinamine substituted aromatic(VIII). Removal of the sulfinyl group is effected by treatment of (VIII)with an acid, such as trifluoroacetic acid, in a solvent such asdichloromethane or HCl in dioxane, at around room temperature, to yieldthe corresponding primary amine (IX).

The primary amine (IX) can be further functionalized using a variety ofprocedures. For example, protection of (IX) as a BOC or otherappropriate derivative (Greene's Protective Groups in Organic Synthesis;4th Edition: John Wiley & Sons, Inc., 2006) provides the carbamate (X).The carbamate is treated with an alkylating agent, such as an alkylhalide or alkyl-sulphonate, in the presence of abase, such as sodiumhydride or potassium carbonate, in a solvent such as THF, DMF, DMA oracetonitrile, at a temperature between 0° C. and about 100° C. to givethe N-alkylated derivative (XI). Oxidative cleavage of the olefin in(XI) is accomplished by treatment with catalytic amounts of osmiumtetroxide (Org. Synth. Oxid. Met. Compd. (1986), 633-93. Plenum, N.Y.)in the presence of a co-oxidant such as N-methyl morpholine N-oxide, ina solvent system, such as tert-butanol/water or acetone/water, to givethe corresponding vicinal di-hydroxy-derivative. This diol is thencleaved using sodium periodate, in a solvent such as THE/water, ataround room temperature, to give (XII).

Installation of a second amino functionality is accomplished bytreatment of (XII) with a secondary amine (R⁴R⁵NH), in the presence of areducing agent (Organic Reactions, Vol. 59, E. W. Baxter & A. B. Reitz,Wiley 2002), such as NaBH₄, NaCNBH₃ or Na(AcO)₃BH, in a solvent such asdichloromethane, methanol, 1,4-dioxane, THF or acetic acid (or acombination thereof) at around room temperature or below, to give(XIII). (XIII) is converted to the requisite carboxylic acid by first,removal of the benzyl protecting group, typically by a hydrogenolysisreaction, using a heterogeneous catalyst, such as palladium on carbon,in a solvent such as ethyl acetate, THF methanol or acetic acid under ahydrogen atmosphere (1-5 bar) to yield the primary alcohol. This alcoholis oxidized to the corresponding acid using a two-step procedure;involving initial oxidation to the aldehyde, using a DMSO based oxidantsystem, such as Swern oxidation (Organic Reactions. (1990), 39,297-572.) or by treatment with excess Des s-Martin periodinane (Journalof Organic Chemistry. (1983), 48, 4155) in a solvent such asdichloromethane at around room temperature. Subsequent oxidation of theintermediate aldehyde is accomplished by treatment with sodiumchlorite/NaH₂PO₄ and 2,3-dimethyl-but-2-ene in a solvent such ast-butanol/water at around room temperature (Journal of OrganicChemistry, (1980), 45, 4825). In certain cases, the primary alcohol mayalso be oxidized to (IV) directly, using one of a number of oxidationprotocols, such as with NaIO₄ and catalytic RuCl₃, in a solvent mixtureof water/CCl₄/CH₃CN in the ratio 3/2/2, at around room temperature(Journal of Organic Chemistry, (1981), 46(19), 3936-8) or withpyridinium dichromate in DMF (Tetrahedron Letters, (1979), 20 (52): 399)at around room temperature.

In the case where Y₁=an optionally substituted 1,2-diamino-ethyl, therequisite acids (IV) are prepared (SCHEME 4) from a suitable aryl-halide(M=I, Br, CO or aryl-triflate (M=O₃SCF₃) (XIV) by treatment with anappropriate vinyl-boronic (XV) acid in the presence of a base such asNa₂CO₃, Cs₂CO₃, Na₃PO₄ and a palladium catalyst such as (Ph₃P)₄Pd,Dppf/Pd(OAc)₂ or the PEPPSI catalyst system, in a solvent such asaqueous 1,4-dioxane, DME, THF, at around room temperature to 100° C. togive the olefin derivative (XVI) (Journal of Organometallic Chemistry,(1999), 576, 147-168). Treatment of (XVI) with sodium azide, in thepresence of a mild oxidant, such as Mn(OAc)₃(H₂O)₂ and an acid such asacetic acid or trifluoroacetic acid, in a solvent such as acetonitrile,at a temperature between −30° C. and 0° C. provides the diazide (XVII)(Synthetic Communications, 28(10), 1913-1922; 1998).

Subsequent reduction of the bis-azide by treatment with a reducingagent, such as triphenylphosphine, in a solvent such as THF, followed byin situ hydrolysis of the intermediate aza-phosphorane with excess wateryields the bis-amine (XVIII). In certain instances, reduction of thebis-azide is achieved by treatment of (XVII) with hydrogen gas, in thepresence of a catalyst, such as palladium on carbon, in a solvent suchas THF or methanol. Subsequent functionalization of (XVIII) isaccomplished as described above to yield (XIX). In particular, in thecase where R4 constitutes part of a piperazine ring structure, (XVIII)is treated with an alkyl-dihalide, such as 1,2-dibromoethane, in thepresence of a base, such as triethylamine, in a solvent such as aqueousTHF or dichloromethane, at around room temperature, to give (XIXa). Theintermediate (XIXa) is converted to (XIXb) as described above. Therequisite acids (IV) are obtained from the corresponding esters (XIX orXIXb) by formal hydrolysis of the ester functionality. The reactionconditions employed depends on the type of the ester used. In the caseof a methyl, ethyl or other simple alkyl, hydrolysis is usually achievedby brief treatment with an aqueous base, such as sodium or lithiumhydroxide in a solvent mixture of THF, water and methanol. However,other acid protecting groups can also be used, such as benzyl,2-trimethylsilyl-ethyl or 2,2,2-trichloroethyl. In these cases,conversion of the ester to the corresponding acid is achieved using thestandard deprotection procedures in the literature (Greene's ProtectiveGroups in Organic Synthesis. Fourth Edition. John Wiley & Sons, Inc.2006).

Alternatively, the 1,2 diamino-ethyl substructure can be prepared from asuitable aryl-alkyl ketone such as (XX) (SCHEME 5). For example,treatment of (XX) with trimethylsilyl-triflate, in ether, at about 0°C., in the presence of triethylamine provides silyl-enol ether (XXI).Treatment of (XXI) with a halogenating reagent, such as bromine, NCS, orpyridinium tribromide in an inert solvent such as dichloromethane orcyclohexane, at a temperature between −78° C. and room temperaturefurnishes the α-halo-ketone (XXII). (XXII) is condensed with an amine(NHR4R5) in an inert solvent such as toluene, THF, acetonitrile or DMA,at room temperature or above, to yield the α-amino-ketone (XXIII).Reductive amination of (XXIII) as described above, yields thediamino-ethyl derivative (XXIV) which is further processed (benzyl etherremoval and oxidation) to provide the requisite acid (IV) as describedabove.

In the case where Y₁ is a 1,2-diamino-substituted-propyl or butyl group,the requisite alkene substrates for the aforementioned chemistry areprepared from the appropriate phenyl-halide (I, Br, CO or triflate andan allyl or buten-yl Grignard in the presence of a copper catalyst suchas CuBr:DMS in a solvent such as THF at around room temperature.

In a variant of the 1,2-diamino system wherein, Y₁ is an amino-alkyl. Y₂is an amino alkyl such that the substituent on the amine bearing carbonof Y₁ and the substituent on the amine bearing carbon of Y₂ togetherform a ring, the requisite acids (IV) are prepared from the appropriatebenzo-fused cyclic alkene (XXV) (SCHEME 6). Bis azidination of (XXV)provides the cyclic bis azide (XXVI) which is processed as previouslydescribed to provide the requiste acid (IV).

In the case where Y₁=an optionally substituted amino-alkyl-amino, therequisite acids (IV) are prepared (SCHEME 7) by cross coupling of anappropriate aryl bromide (XXVII, M=Br), aryl iodides (XXVII; M=I), arylchlorides (XXVII; M=CO or aryl-sulphonate ester (XXVII; M=O₃SR) with adiamine (or mono-N-protected-diamine) (XXVIII) (Metal-Catalyzed CrossCoupling Reactions, 2^(nd) Ed., Wiley-VCH: 2004) to give intermediate(XXIX). This is followed by hydrolysis of the ester functionality togive (IV). The cross coupling of (XXVII) with amines is generallycarried out under palladium catalysis, using a palladium source such aspalladium bis(dibenzylidineacetone),Tris(dibenzylideneacetonyl)bis-palladium or palladium diacetate in asolvent such as toluene, THF, DMF or DMA at temperatures between 80 and110° C. in the presence of a base such as sodium t-butoxide, potassiumphosphate or lithium hexamethyldisilazide and a ligand such as2-dicyclohexyl-phosphino-2′-dimethylamino-biphenyl,2,2′-Bis(diphenyl-phosphino)-1,1′-binaphthylene,9,9-Dimethyl-4,5-bis(diphenylphosphino)-xanthene,tri(tert-butyl)-phosphine, 2-(Di-tert-butylphosphino)-1,1′-biphenyl,2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane,2-methyl-N,N′-bis(isobutyl)-2-[[(isobutyl)amino]-methyl]-1,3-propanediamineor the PEPPSI system (Chemical Society Reviews, (2011), 40, 5151-5169).In certain cases, cross coupling of (XXVII) and (XXVIII) employs acopper catalyst, such as Copper iodide and a 1,3 dicarbonyl ligand suchas 2-isobutyryl-cyclohexanone in DMF in the presence of a base such asCs₂CO₃ at a temperature between room temperature and 100° C. In the casewhere M is a nonaflate, the base is generally DBU or MTBD(7-methyl-1,5,7-triazabicyclo-[4.4.0]-dec-5-ene) and the ligands are2,4,6,-triisopropyl-2′ dicyclhexylphosphino-biphenyl or9,9-Dimethyl-4,5-bis(diphenylphosphino)-xanthene in a solvent such astoluene, at a temperature of 100-150° C. (Journal of Organic Chemistry(2006), 71, 430.)

The N-protecting group employed in (XXVIII) is generally a carbamate,such as tert-butyl, benzyl or 2-trimethylsilyl-ethyl. Removal of suchgroups employs standard conditions described in the literature (Greene'sProtective Groups in Organic Synthesis, Fourth Edition, John Wiley &Sons, Inc., 2006).

In the case where Y₁=an optionally substituted amino-alkyl and Y₂ is,independently, an optionally substituted amino alkyl, the requisiteacids ((IV), FIGURE 1) are usually prepared by sequential introductionof the amine functionality into the corresponding hydroxyl or oxosubstituted carbon scaffold. The conversion of a hydroxyl functionalgroup to an amine is accomplished by one of a number of reactionsequences known in the literature (Comprehensive OrganicTransformations, VCH publishers. 1989). These generally involveconversion of the alcohol to a leaving group, such as an iodide,bromide, benzenesulphonate, mesylate or triflate, followed bydisplacement of the leaving group using an azide anion salt, such assodium azide or tetrabutylammonium azide, in a solvent such as DMF, DMADMSO or acetonitrile. The azide is then reduced to the correspondingprimary amine by hydrogenation or Staudinger reaction, as describedabove. Alternatively, Introduction of the primary amino functionality iseffected by conversion of the alcohol functionality to the correspondingpthalimide under Mitsunobu conditions (Chemical Reviews, (2009)2551-2651), followed by deprotection of the pthalimide by treatment withexcess hydrazine, in a solvent such as ethanol, at room temperature orabove.

Conversion of an oxo functionality to the corresponding amine isachieved by reductive amination or t-butylsulphinimide formation andhydride addition/alkylation of the C═N functionality of the imine(Chemical Reviews, (2010), 110(6), 3600-3740). In a special case wherethe oxo is part of a carboxylic acid group, the amine functionality canbe introduced by a Curtius rearrangement. (Tetrahedron (1974), 30 (14):2151-2157).

The appropriate hydroxyl or oxo substituted carbon scaffold is preparedby one of a wide range of sequences known in the literature. Thesequence employed in any given case depends on the specific arrangementof diamine functionality required. For example, in the case where p=0and m=2 (IV), FIGURE 1), the carbon scaffold is prepared as illustratedin SCHEME 8. Treatment of the 3-bromo-4-formyl-benzoate (XXX) with asecondary amine (R3R4NH) in the presence of a reducing agent such assodium borohydride, as previously described, provides the benzylic amine(XXXI). Exposure of this intermediate to methyl-vinyl ketone under theconditions of the Heck reaction yields the α,β-unsaturated ketone(XXXII). Reduction of (XXXII) using a Pd, Rh or Pt catalyst, such as 10%Pd on carbon, or Wilkonson's catalyst under an atmosphere of hydrogengas (1-4 atm), in a solvent such as toluene, ethyl acetate, methanol orTHF (or a mixture thereof) at room temperature to 70° C. gives thesaturated ketone (XXXIII). Alternatively, unsaturated-ketone (XXXII) isreduced by treatment with excess Magnesium, in a solvent such asmethanol, at around room temperature (Tetrahedron Letters, (1986);27(21), 2409-2410). Reductive amination of (XXXIII) with a secondaryamine (R4′R5′NH), as described above provides (XXXIV). Finally,hydrolysis of the ester functionality in (XXXIV) yields the requisiteacid (IV).

In addition to alcohol or carbonyl derivitization, the aminofunctionality may also be introduced, in latent form (such as a nitro,cyano, or amide) or directly during a C—C bond forming reaction employedin the construction of the carbon framework. For example (SCHEME 9),coupling of the aryl chloride (XXXV) with potassium(BOC-aminomethyl)-trifluoroborate in the presence of Pd(OAc)₂ and aphosphine ligand such as SPhos or XPhos and a base, such as potassiumcarbonate, in a solvent mixture of toluene and water, yields thebenzyamine derivative (XXXVI) (Organic Letters, (2011), 13(15),3956-3959). Functionalization of the BOC amine is achieved as describedabove to give (XXXVII). Coupling of this intermediate with asilyl-nitronate (XXXVIII) in the presence of a fluoride ion sourceprovides the nitroaldol product (XXXIX) (European Journal of OrganicChemistry, (2007), 16, 2561-2574). Reduction of (XXXIX) with lithiumaluminum hydride in THF yields the bis-amine (XL). This intermediate isagain derivatized as described above to yield (XLI). (XLI) is thenconverted to the corresponding acid (IV) as described above.

In the case where Y₁=an optionally substituted amino-alkyl and Y₂ is anoptionally substituted amino group, the requisite acids (IV) areprepared from the corresponding bromide (XXVI) (SCHEME 10) by apalladium catalyzed amination as described above (Metal-Catalyzed CrossCoupling Reactions, 2^(nd) Ed., Wiley-VCH: 2004) as illustrated inSCHEME 7.

In a variant of this system wherein, Y₁=a substituted amino-alkyl and Y₂is a substituted amino group, such that the substituent on theamine-bearing carbon of Y₁ and N-substituent of Y₂ together form a ring,the requisite acids (IV) (SCHEME 11) are prepared, using a Povarovreaction, (Name Reactions in Heterocyclic Chemistry II, (2011), 385-399Wiley) from the appropriately substituted aniline (XLIII), aldehyde orketone (XLIV) and an N-vinyl carbamate (XLV) in the presence of an acidsuch as a diaryl phosphoric acid ester (for example, the phosphoric acidester of BINOL (Journal of the American Chemical Society, (2011),133(37), 14804-14813) in a solvent such as dichloromethane at around 0°C. to give (XLVI). Subsequent derivatization of the amine functionalityin (XLVI), as previously described, followed by ester hydrolysis yields(IV).

In the case where Y₁=an optionally amino substituted piperidine and Y₂is a H, the requisite acids (IV) (SCHEME 12) are prepared by reaction ofan aryl Grignard reagent such as (XLIX) with an appropriately protectedsulphinimide such as (XLVIII), as previously described, to provideintermediate (L). Treatment of (L) with an acid such as TFA indichloromethane or HCl in dioxane yields the deprotected amino ester(LI). Boc protection of (LI), followed by conversion of the primaryalcohol to the corresponding tosylate, using standard methods, yields(LII). Treatment of (LII) with a base such as K₂CO₃, NaH, DBU or TMG ina solvent such as DMA, NMP or DMF effects cyclization to give (LIII).(LIII) is de-protected and derivatized, as previously described, toyield the requisite acid (IV).

In a variant of this system, wherein Y₁=hexahydropyriminin-2-imine andY₂ is a H, the requisite acids (IV) (SCHEME 13) are prepared bycondensation of a 2-phenyl-1,3 diamino-propane (LIV) derivative with2-Methyl-2-thiopseudourea sulfate (LV) (Journal of Medicinal Chemistry,(1985), 28(6), 694-8) to give (LVI) which is processed to give (IV) aspreviously described. The requisite 1,3 diamine (LIV) is obtained byHofmann degradation of the bis amide (LVII); by introduction of thediamine functionality into the corresponding hydroxyl-substituted carbonscaffold (LVIII) as previously described (Organic Letters, (2207),9(21), 4203-4206) or by reduction of the di-nitro derivative (LIX) witha hydride donor, such as lithium aluminum hydride, in a solvent such asTHF. The di-nitro derivative is obtained from an appropriatealdehyde/ketone by condensation with nitromethane in the presence ofalumina at room temperature (European Journal of Organic Chemistry,(2010), (3), 483-493) or by a nitro-alkene silyl-nitronate condensationin the presence of a quaternary ammonium fluoride ion source (AngewandteChemie International Edition, (2006), 45, 7606-7608).

In the case where Y₁=an optionally amino-alkyl-substituted piperidine,the requisite acids (IV) (SCHEME 14) are prepared by alkylation of anappropriately substituted phenyl-acetonitrile, phenyl-acetone or phenylacetic acid derivative such as (LX) with a bis-(chloroalkylamine), inthe presence of a base such as, sodium hydride, potassium t-butoxide orsodium hydroxide, in a solvent such as THF, DMSO, toluene or DMF. In thecase where aqueous NaOH is the base, a phase transfer catalyst, such asmethyl-trioctanylammonium chloride can also be used (Journal ofHeterocyclic Chemistry, (1986), 23(1), 73-5) to provide (LXI).

Functionalization of the iodide/bromide in (LXI) with a vinyl or allylstannane, in a solvent such as DMF, in the presence of a palladiumcatalyst, such as (Ph₃P)₄Pd, yields the olefin functionalized piperidine(LXII). Treatment of (LXII) with a strong reducing agent such as lithiumaluminum hydride, in a solvent such as THF or glyme, provides4,4-disubstituted piperidine (LXIII). Derivitization of the aminefunctionality to give (LXIV) is achieved as already described.Installation of the carboxyl functionality to give (IV) is accomplishedby hydroboration/oxidation to give the corresponding primary alcohol; oroxidative cleavage of the olefin functionality to give the one carbontruncated aldehyde, followed by further oxidation to the acid aspreviously described.

In a particular variant of this system, Y₁=a 4-substituted piperidineand Y₂ is a substituted amine such that the substituent on the 4position of the piperidine and the substituent on the (Y₂) aminetogether form a ring, the requisite acids (IV) (SCHEME 15) are preparedfrom an appropriately substituted 2-fluoro-aryl/heteroarylacetonitrile(Tetrahedron, (2004), 60(22), 4874-4878). For example, treatment of abromo or iodo substituted 2-fluoro-acetonitrile (LXV) with abis-(2-chloroethyl)-amine derivative, as described above, provides thepiperidine (LXVI). Functionalization of the iodide/bromide with a vinylor allyl stannane, in a solvent such as DMF, in the presence of apalladium catalyst, such as (Ph₃P)₄Pd, yields the olefin functionalizedpiperidine (LXVII). Treatment of (LXVII) with a strong reducing agentsuch as lithium aluminum hydride/ethanol in a solvent such as glyme,provides the spiro-indole (LXVIII).

Derivitization of the amine functionality to give (LXIX) is achieved asalready described. Installation of the carboxyl functionality to give(IV) is accomplished by oxidation of the olefin functionality aspreviously described.

In another variant of this system, Y₁=a 4-substituted piperidine suchthat the substituent on the 4 position of the piperidine and the orthosubstituent on A, taken together, form a carbocyclic ring. In thisinstance, the requisite acids (IV) (SCHEME 16) are prepared from anappropriate aryl fused cyclopentadiene. For example, Treatment of (LXX)with a bis-(2-chloroethyl)-amine derivative in the presence of a strongbase, such as LHMDS, in a solvent such as THF, at around 0° C., yieldsthe spiro-cyclopentadiene (LXXI)) (Bioorganic and Medicinal ChemistryLetters, (2012), 22(1), 363-366). Hydroboration of the olefin with 9-BBNin THF at around 0° C. followed by oxidative work up (NaOH/H₂O₂)provides the

hydroxyl derivative (DOW). Derivitization of the alcohol functionality,as described above, yields the diamine derivative (LXXIII). Installationof the acid functionality is accomplished, as described above, viaStille coupling of the bromide with an allyl or vinyl stannane followedby oxidation the olefin group and further oxidation of the resultingalcohol/aldehyde to the corresponding acid.

In the case where Y₁ is a piperidin-4-yl-substituted C1-C3 alkyl, Y₂ isa C1-amino-alkyl group such that the C4 of the piperidine of Y₁ and theC1-alkyl group of Y₂ are connected through a bond to form a 5, 6 or 7membered ring, the requisite acids (IV) (SCHEME 17) are prepared fromthe appropriately substituted aryl/heteroaryl fused-carbocyclic ketone.For example, treatment of ketone (LXXIV) with a substitutedbis-(bromoethyl)-amine in the presence of a base such as NaH, in asolvent such as DMF, DMA or NMP at around 50° C. (Bioorganic & MedicinalChemistry Letters, (2010) 20(2), 746-754) yields thespiro-piperidine-ketone (LXXV). Installation of a second aminofunctionality is achieved by treatment of (LXXV) with an amine(NHR4′R5′) in the presence of a Lewis acid such as TiCl_(n)(OiPr)_(4-n)(n=0-4) in a solvent, such as benzene, at a temperature between roomtemperature and reflux to give imine (LXXVI) (European Journal ofOrganic Chemistry, (2007), 18, 2945-2957. Journal of the ChemicalSociety, Perkin Transactions 1: Organic and Bio-Organic Chemistry(1988), 12, 3399-406). The imine (LXXVI) is reduced with a hydridereducing agent such as NaBH₄ or LiBH₄ in a solvent such as THF, glyme ormethanol to give (LXXVIII). Alternatively, treatment of (LXXV) withLHMDS to form the N-trimethylsilylimine (LXXVII) in situ, followed byreduction with NaBH₄ or LiBH₄ in a solvent such as THF provides theprimary amine (LXXIX) which is then derivatized as already described. Athird approach involves treatment of (LXXV) with NaBH₄ or LiBH₄ followedby reaction of the resulting alcohol (LXXX) with diphenylphosphorylazide, in the presence of DBU, in a solvent such as benzene or tolueneat around 0° C. followed by a period of heating at a temperature between50 and 100° C. to give azide (LXXXI). The azide is reduced and theresulting primary amine (LXXIX) and derivatized as previously described.Processing of the benzyloxyalkyl side chain in (DOOM) to provide (IV) isaccomplished as described previously.

In a variant of this system, where Y₁ is an amino substituted C2-C4alkyl, Y₂ is a piperidin-4yl group such that the C-4 substituent on thepiperidine of Y₂ and the amino substituted carbon of Y₁ together forma5, 6 or 7 membered ring, the requisite carboxylic acids (IV) (SCHEME 18)are prepared from the appropriate cyclic ketone (LXXXIII) usingessentially the same methods for piperidine ring formation and amineinstallation as described above

In a particular variant of this system, where Y₁ is a di-basic orcationic substituted C3-C4 alkyl, such that the C2 substituent on Y₁ andthe substituent on ArA, positioned ortho-to Y₁, together form a ring,the requisite carboxylic acids (IV) (SCHEME 19) are prepared from theappropriate ary/heteroaryl-fused carbocyclic ketone (LXXXIV). Forexample, formation of the silyl-enol ether of (LXXXIV), under standardconditions, followed by condensation of the silyl enol ether with anappropriate nitro-alkene in the presence of a Lewis acid, such asTiClnOiPr4-n (n=0-4), in a solvent such as dichloromethane, provides thenitro-ethyl-substituted ketone (LXXXV) (Journal of the American ChemicalSociety, (1984) 106(7), 2149-56). Reduction of (LXXXV) with a hydridedonor such as lithium aluminum hydride in THF yields the amino alcohol(LXXXVI). Derivatization of the primary amino group of (LXXXVI), aspreviously described, yields the alcohol (LXXXVII). Conversion of thealcohol to the azide and then the derivatized amine as previouslydescribed provides the diamine (LXXXVIII). This intermediate isprocessed to yield (IV) as described above. Similarly, reaction of thesilyl-enol ether derived from (LXXXIV) with an amine acetal(Tetrahedron, (1988), 44(13), 4157-4172) in the presence of TMSOTfprovides (LXXXIX) which is processed, via (XC) to provide (IV) asdescribed above.

In the case where Y₁ is an amino or aminomethyl-substituted pyrrolidine,the requisite carboxylic acids (IV) (SCHEME 20) are prepared from theappropriate cinnamate (XCI) and anN-(methoxymethyl)-N-(trimethylsilylmethyl)-amine derivative (XCII) inthe presence of an acid, such as TFA, in a solvent such as toluene ordichloromethane, at 0° C. or above to give (XCIII). Ester (XCIII) isprocessed, via ester hydrolysis and a Curtius rearrangement, to provide(XCIV) or by amide formation to give (XCV) and reduction of the amidecarbonyl to yield (XCVI) as previously described. The intermediate(XCIV) is derivitized to give (XCVII). Intermediates (XCV) and (XCVII)are converted to the corresponding acids (IV) by benzyl ether removaland oxidation of the resulting primary alcohol as previously described.

In a variant of this system, wherein Y₁ is a 3-amino or3-aminomethyl-substituted piperidin-5-yl group, the requisite carboxylicacids (IV) (SCHEME 21) are prepared by treatment of an appropriatephenyl acetic acid ester (XCVIII) with a strong base, such as LDA orLHMDS, in a solvent such as THF, at a temperature between −78° C. and 0°C. to form the enolate, then reaction of this intermediate with asuitable 2-(N,N-dibenzylamino)-methacrylate (XCIX) ester to give (C).debenzylation of (C) by hydrogenolysis, as described above followed bycyclization of the resulting primary amino ester in the presence of abase such as DBU or TMG in a solvent such as toluene at a temperaturebetween room temperature and 100° C. provides the lactam (CI).

Derivitization of the amide nitrogen in (CI) and reduction of the amidecarbonyl, as already described, provides piperidine (CII). Processing ofthe ester functionality in (CII) to yield (CIII) or (CIV) is carried outas previously described. Removal of the MOM protecting group, understandard conditions, followed by oxidation of the resulting primaryalcohol provides the requisite acids (IV).

In the case where, Y₁ is an amino substituted alkoxy, and Y₂ is anamidine linked to the aryl ring through carbon, the requisite acids (IV)(SCHEME 22) are prepared from the appropriate cyano-substituted-phenol(CV) by treatment with a suitably functionalized alcohol (CVI) in thepresence of an azodicarboxylate ester such as DEAD or DIAD and aphosphine such as Ph₃P, in a solvent such as THF under the Mitsunobureaction conditions to give (CVII). De-protection of the latent carbonylfunctionality in (CVII) under standard conditions provides (CVIII).Subsequent processing of (CVIII) yields the corresponding amine (CIX).Conversion of (CIX) to the amidine (CX) is accomplished by treatmentwith HCl in methanol to form the corresponding imidate ester followed byreaction of this intermediate with an appropriate amine (R⁴R⁵NH), in asolvent such as methanol or THF at around room temperature. Furthermore,in the case where R⁴R⁵NH above is ammonia, the amidine functionality canalso be introduced by treatment of the nitrile (CIX) with hydroxylamineto give the corresponding N-hydroxyl-amidine. This is followed bycatalytic hydrogenolysis (Pd on carbon in acetic acid/acetic anhydride)to provide the amidine (CX). Acylation of the amidine functionality in(CX) and selective hydrolysis of the ester functionality yields (IV).

In the case where In the case where Y₁ is (or contains) a guanidine, theguanidino group is derived from the appropriate primary or secondaryamine (CXI) (SCHEME 23) by treatment with a reagent such as1,3-Di-tert-butyloxy carbonyl-S-methylisothiourea, in a solvent such asDMF, (Synthesis, (2004), 37-42) or pyridine at room temperature orabove, or by treatment with N,N′ Bis-(BOC)-1H-pyrazole-1-carboxamidinein the presence of abase such as diisopropylethylamine, in a solventsuch as DMF or DMA at around room temperature to give (CXII). Selectivecleavage of the ester functionality in (CXII), as already described,provides the corresponding acid (IV). Similarly, primary or secondaryamine (CXI) is converted to the amidine functionality by treatment witha suitable alkyl thioimidate, such as the 2-napthylmethylthioimidatederivative (XVI), in a solvent such as ethanol at a temperature between0° C. and room temperature (Tetrahedron Letters, (1997), 38(2), 179-182)to give (CXIII). Protection of the amidine (CXIII) as a carbamatederivative, such as BOC or Cbz (CXIV) under standard conditions,followed by selective ester hydrolysis provides acid (IV).

In certain instances, it is convenient to assemble Y₁ and or Y₂ prior toformation of the heteroaromatic ring. For example, in the case where ArAis a 1,2,3-triazole, the requisite carboxylic acids (IV) (SCHEME 24) areprepared by condensation of an appropriately substituted alkyne (CXV)with an appropriately substituted azide (CXVI) in the presence of acopper catalyst (Chemical Society Reviews (2010), 39(4), 1302-1315) suchas copper sulphate/sodium ascorbate, in a solvent such as DMF/water togive (CXVII). Cleavage of the ester functionality in (CXVII) aspreviously described, provides (IV).

In the case where ArA is a thiazole, the requisite carboxylic acids (IV)(SCHEME 25) are prepared from an appropriately substitutedprimary-thioamide/thiourea (CXVIII) and an appropriately substituted a-halo-ketone (CXIX) in a solvent such as toluene, at a temperaturebetween room temperature and 120° C. to give (CXX). Cleavage of theester functionality in (CXX) as previously described provides (IV).

In the case where Z is a sulphonyl group (SCHEME 26), the requisitesulphonic acid is prepared from the corresponding activated carboxylicacid (V) by treatment with sodium hydroxythiopyridone in a solvent suchas dichloromethane, at around room temperature to yield the Barton esterintermediate (CXXI). (CXXI) is treated with iodoform in CCl₄ under atungsten UV lamp at around reflux temperature to provide thede-carboxylative-iodination product (CXXII) (Journal of OrganicChemistry, 75(19), 6489-6501; 2010). Alternatively, treatment of acid(IV) with iodoso-benzene-diacetate and iodine in CCl₄, under a tungstenUV lamp, at around reflux temperature (Journal of Organic Chemistry,(1986), 51, 402) provides (CXXII) directly. Treatment of (CXXII) withsodium sulphite in aqueous ethanol, isopropanol or acetone, at atemperature between 60 and 90° C., followed by acidification yields thesulphonic acid (IV). Alternatively, treatment of (CXXII) with thioureain acetone, at around 60° C., provides the is othiouronium saltderivative (CXXIII) (Synthetic Letters, (2010), 7, 1037). Cleavage of(CXXIII) with aq. sodium thiosulphate gives thiol (CXXIV). Treatment of(CXXIV) with performic acid (formic acid and aqueous H₂O₂ at around 0°C. to room temperature) provides (IV).

The requisite amines (III) are prepared according to literature methods(WO2010/130708).

Synthetic Examples

The following preparations of compounds of Formula I or Formula Ia andintermediates are given to enable those of skill in the art to moreclearly understand and to practice the present invention. They shouldnot be considered as limiting the scope of the invention, but merely asillustrative and representative thereof.

Example 1.(R)-2-hydroxy-3-(1-phenylcyclopropanecarboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis oftert-butyl3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-2-(1-phenylcyclopropanecarboxamido)ethyl)-2-methoxybenzoate

To anhydrous CH₂Cl₂ (0.61 mL, 9.4 mmol) in THF (20 mL) under Argon at−100° C. (MeOH/Liq. N₂) was added n-BuLi (2.7 mL, 2.5 M in hexane)dropwise and the reaction mixture was stirred at same temperature for 30min. A THF (5 mL) solution of2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester (2.37 g, 5.92 mmol) was added over a period of 10min. After 20 min, the cooling bath was removed and the reaction mixturewas slowly warmed up to 0° C. and stirred at same temperature for 1 hr.The reaction mixture was then cooled to −78° C., LHMDS (8.0 mL, 1M inTHF) was added slowly and the resultant reaction mixture was stirredwhile warming up to room temperature gradually overnight. Anhydrous MeOH(0.29 mL, 7.1 mmol) was added at −10° C., the reaction was stirred atsame temperature for 1 hr and then at room temperature for 1 hr.

In a separated flask containing 1.1 g of 1-phenylcyclopropanecarboxylicacid (6.8 mmol), anhydrous CH₂Cl₂ (15 mL) was added. To this reactionmixture was added NMM (0.92 mL, 8.4 mmol), followed by HATU (2.66 g, 7.0mmol). DMF (1 mL) was added and the resultant solution was stirred atroom temperature for 1 hr, at which time the solution from abovereaction was added to the flask and the reaction was stirred for 2 hr.The reaction was quenched by addition of water (50 mL) and the aqueousphase extracted with EtOAc (3×50 mL). The organic phase was washed withbrine, dried over Na₂SO₄, and concentrated in vacuo to afford the crudeproduct, which was purified by flash chromatography on silica gel toafford the product (1.0 g, 29%)

Step 2.(R)-2-hydroxy-3-(1-phenylcyclopropanecarboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

To a solution of tert-butyl3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-2-(1-phenylcyclopropanecarboxamido)ethyl)-2-methoxybenzoatefrom step 1 (200 mg, 0.35 mmol) in anhydrous CH₂C (5 mL) at −78° C. wasadded BCl₃ (2.5 mL, 1M in DCM, 2.5 mmol), and the reaction mixture wasstirred at same temperature for 1 hr, at which time the reaction mixturewas warmed up to 0° C. and stirred at same temperature for additional 1hr. The reaction was quenched by addition of water (5 mL) at 0° C. Theaqueous phase was extracted by EtOAc. The organic phase was washed withbrine, dried over Na₂SO₄, and concentrated. The crude product wasrecrystallized in EtOAc/Hexane to afford the product (35 mg) as whitesolid. ESI-MS m/z 352 (MH)⁺.

Example 2:(R)-3-(2,2-difluoro-2-phenylacetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-3-(2,2-difluoro-2-phenylacetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 2,2-difluoro-2-phenylacetic acid following theprocedure described in step 1 and step 2 of Example 1 to afford theproduct (5.5 mg) as white solid. ESI-MS m/z 362 (MH)⁺.

Example 3:(R)-2-hydroxy-3-(4-phenylpiperidine-4-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis oftert-butyl4-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyphenyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethylcarbamoyl)-4-phenylpiperidine-1-carboxylate

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid followingthe procedure described in step 1 of Example 1. The crude product waspurified by flash chromatography on silica gel (Hexane/EtOAc, 2:1 to1:2). ESI-MS m/z 717.1 (MH)⁺.

Step 2. Synthesis of(R)-2-hydroxy-3-(4-phenylpiperidine-4-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

To a solution of the product from step 1 (460 mg, 0.64 mmol) inanhydrous CH₂C12 (15 mL) at −78° C. was added BCl₃ (5.0 mL, 1M in DCM,5.0 mmol), and the reaction mixture was stirred at same temperature for1 hr, at which time the reaction mixture was warmed up to 0° C. andstirred at same temperature for additional 1 hr. The reaction wasquenched by addition of water (5 mL) at 0° C. After the phaseseparation, the product in aqueous phase was purified by reverse phasepreparative HPLC [Phenomenex Luna, 5 μm, 30×75 mm, 5-100% AcCN:H₂O (with0.1% TFA)] and dried using lyophilization to afford the product (10 mg)as while solid. ESI-MS m/z 395 (MH)⁺.

Example 4:(R)-2-hydroxy-3-(4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-2-hydroxy-3-(4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylicacid following the procedure described in step 1 and step 2 of Example3. The final product was purified by reverse phase preparative HPLC anddried using lyophilization. ESI-MS m/z 373 (MH)⁺.

Example 5:(R)-3-(2-borono-2-(1,2,3,4-tetrahydroisoquinoline-6-carboxamido)ethyl)-2-hydroxybenzoicacid

Synthesis of(R)-3-(2-borono-2-(1,2,3,4-tetrahydroisoquinoline-6-carboxamido)ethyl)-2-hydroxybenzoicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acidfollowing the procedure described in step 1 and step 2 of Example 3. Thefinal product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 367 (MH)⁺.

Example 6:(R)-2-hydroxy-3-(6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-2-hydroxy-3-(6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

To(R)-3-(2-borono-2-(4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamido)ethyl)-2-hydroxybenzoicacid (10.0 mg from Example 4) in MeOH (5 mL) was added formaldehyde (1.0mL, 37% solution), followed by 10% Pd/C (20 mg). The reaction mixturewas hydrogenated under H₂ balloon for 3 hr. The reaction mixture wasfiltrated and the solvent was removed under vacuum. The final productwas purified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 387 (MH)⁺.

Example 7:(R)-2-hydroxy-3-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-2-hydroxy-3-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from(R)-3-(2-borono-2-(1,2,3,4-tetrahydroisoquinoline-6-carboxamido)ethyl)-2-hydroxybenzoicacid (from Example 5) using the procedure described in Example 6. Thefinal product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 381 (MH)⁺.

Example 8:(R)-2-hydroxy-3-(1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-2-hydroxy-3-(1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acidfollowing the procedure described in step 1 and step 2 of Example 3. Thefinal product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 352 (MH)⁺.

Example 9:(R)-2-hydroxy-3-(isoindoline-5-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of benzyl5-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyphenyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethylcarbamoyl)isoindoline-2-carboxylate

Prepared from 2-(benzyloxycarbonyl) isoindoline-5-carboxylic acidfollowing the procedure described in step 1 Example 3. The crude productwas purified by flash chromatography on silica gel (Hexane/EtOAc, 2:1 to1:2). ESI-MS m/z 709.1 (MH)⁺.

Step 2. Synthesis oftert-butyl3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-2-(isoindoline-5-carboxamido)ethyl)-2-methoxybenzoate

To benzyl5-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyphenyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethylcarbamoyl)isoindoline-2-carboxylate(250 mg) in MeOH (10 mL) was added Pd on C (25 mg, 10%) and the reactionmixture was stirred under a hydrogen balloon for 4 hr. The catalyst wasfiltered and the solvent removed in vacuo to afford free amine (180 mg,89%). ESI-MS m/z 575.1 (MH)⁺.

Step 3. Synthesis of(R)-2-hydroxy-3-(isoindoline-5-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from tert-butyl3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-2-(isoindoline-5-carboxamido)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 353 (MH)⁺.

Example 10:(R)-2-hydroxy-3-(2-methylisoindoline-5-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-2-hydroxy-3-(2-methylisoindoline-5-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from(R)-3-(2-borono-2-(isoindoline-5-carboxamido)ethyl)-2-hydroxybenzoicacid following the procedure described in Example 6. The crude productwas purified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 367 (MH)⁺.

Example 11:(R)-3-(2-(2-aminoethyl)isoindoline-5-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis oftert-butyl3-((2R)-2-(2-(2-(tert-butoxycarbonylamino)ethyl)isoindoline-5-carboxamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

To tert-butyl3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-2-(isoindoline-5-carboxamido)ethyl)-2-methoxybenzoatefrom Example 9 step 2 (263 mg, 0.46 mmol) in DMF (5 mL) was added K₂C03(252 mg, 1.84 mmol) and tert-butyl 2-bromoethylcarbamate (122 mg, 0.54mmol). The resulting reaction was stirred at room temperature overnight.Water (15 mL) was added and the aqueous phase was extracted with EtOAc.The organic phase was washed with 1N HCl, brine, dried over Na₂SO₄ andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel (Hexane/EtOAc, 2:1 to 1:2). ESI-MS m/z718.1 (MH)⁺.

Step 2. Synthesis of(R)-3-(2-(2-aminoethyl)isoindoline-5-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from tert-butyl3-((2R)-2-(2-(2-(tert-butoxycarbonylamino)ethyl)isoindoline-5-carboxamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 396 (MH)⁺.

Example 12:(R)-2-hydroxy-3-(2-(pyridin-3-ylmethyl)isoindoline-5-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis oftert-butyl2-methoxy-3-((2R)-2-(2-(pyridin-3-ylmethyl)isoindoline-5-carboxamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)benzoate

To tert-butyl3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-2-(isoindoline-5-carboxamido)ethyl)-2-methoxybenzoatefrom Example 9 step 2 (240 mg, 0.42 mmol) in 1,2-dichloroethane (5 mL)was added nicotinaldehyde (90 mg, 0.84 mmol) and Na(OAc)₃BH₄ (211 mg, 1mmol). The reaction mixture was stirred at room temperature for 6 hr.Water (10 mL) was added at 0° C. and the aqueous phase was extractedwith EtOAc. The organic phase was washed brine, dried over Na₂SO₄ andconcentrated in vacuo. The crude product was carried to the next stepwithout further purification. ESI-MS m/z 666.1 (MH)⁺.

Step 2. Synthesis of(R)-2-hydroxy-3-(2-(pyridin-3-ylmethyl)isoindoline-5-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from tert-butyl2-methoxy-3-((2R)-2-(2-(pyridin-3-ylmethyl)isoindoline-5-carboxamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)benzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 344 (MH)⁺.

Example 13:(R)-2-hydroxy-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-2-hydroxy-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and2-(5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acetic acid following theprocedure described in step 1 and step 2 of Example 3. The final productwas purified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 382 (MH)⁺.

Example 14:(R)-3-(3,4-bis(aminomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of 3,4-bis((tert-butoxycarbonylamino)methyl)benzoicacid

Step 1a. Synthesis of methyl 3,4-bis(bromomethyl)benzoate

A solution of 3,4-dimethyl benzoic acid (10 g), NBS (23.6 g) and AIBN(1.0 g) in CCl₄ (110 mL) were heated at reflux for 10 hr. After coolingand filtration, the solvent was removed and the residue was dissolved inDCM (200 mL) and the organic phase washed with water and aqueoussaturated NaHCO₃ solution. The organic phase was dried over Na₂SO₄ andconcentrated in vacuo. The product (20 g) was used directly to the nextstep without further purification.

Step 1b. Synthesis of methyl 3,4-bis(azidomethyl)benzoate

To methyl 3,4-bis(bromomethyl)benzoate (3.24 g, 10 mmol) in EtOH/THF/H₂O(100 mL, 4:2:1) was added NaN₃ (2.00 g, 30 mmol) and the resultantreaction mixture stirred at room temperature overnight. The aqueous wasextracted with EtOAc (100 mL×3). The organic phase was combined, washedwith brine, dried and concentrated. The residue (2.2 g) was useddirectly to the next step without further purification.

Step 1c. Synthesis of methyl 3,4-bis(aminomethyl)benzoate

The crude material from the above step (2.2 g, 20 mmol) was dissolved inMeOH (200 mL) and hydrogenated using Parr at 60 psi for 4 hr. Thereaction mixture was filtrated over Celite and concentrated in vacuo toafford the product (1.5 g) which was used directly in the next stepwithout further purification.

Step 1d. Synthesis of methyl3,4-bis((tert-butoxycarbonylamino)methyl)benzoate

To methyl 3,4-bis(aminomethyl)benzoate (1.0 g, 5.2 mmol) in DCM (10 mL)was added TEA (2.9 mL, 20 mmol) and di-tert-butyl dicarbonate (3.4 g,15.5 mmol). The resultant reaction mixture was stirred at roomtemperature overnight. The organic phase was washed with 1N HCl, brine,dried and concentrated in vacuo. The residue was purified over silicagel to afford the product (1.0 g)

Step 1e. Synthesis of 3,4-bis((tert-butoxycarbonylamino)methyl)benzoicacid

The ester from the above step (1.0 g, 2.5 mmol) was dissolved in amixture of MeOH/THF (50 mL, 2:1). 1N NaOH (10 mmol, 10 mL) was added andthe reaction mixture was stirred at room temperature overnight. 1N HClwas added to adjust the pH of reaction to ˜3. The aqueous layer wasextracted with EtOAc. The organic phase was washed with 1N HCl, brine,dried and concentrated in vacuo to afford the product (0.55 g) as paleyellow solid.

Step 2. Synthesis oftert-butyl3-((2R)-2-(3,4-bis((tert-butoxycarbonylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and3,4-bis((tert-butoxycarbonylamino)methyl)benzoic acid following theprocedure described in step 1 of Example 3. The crude product waspurified by flash chromatography on silica gel (Hexane/EtOAc, 2:1 to1:2). ESI-MS m/z 792.1 (MH)⁺.

Step 3. Synthesis of(R)-3-(3,4-bis(aminomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from tert-butyl3-((2R)-2-(3,4-bis((tert-butoxycarbonylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 370 (MH)⁺.

Example 15:(R)-3-(2-amino-3,4-dihydroquinazoline-7-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of2-(2,4-dimethoxybenzylamino)-3,4-dihydroquinazoline-7-carboxylic acid

Step 1a. Synthesis of Methyl 4-(bromomethyl)-3-nitrobenzoate

Methyl 4-(bromomethyl)-3-nitrobenzoate was prepared following theprocedure described in step 1a in Example 14.

Step 1b. Synthesis of Methyl 4-(azidomethyl)-3-nitrobenzoatenitrobenzoate

Methyl 4-(azidomethyl)-3-nitrobenzoate nitrobenzoate was preparedfollowing the procedure described in step 2 in Example 14.

Step 1c. Synthesis of Methyl 3-amino-4-(aminomethyl)benzoate

Methyl 3-amino-4-(aminomethyl)benzoate was prepared following theprocedure describe in step 3 in Example 14.

Step 1d. Synthesis of methyl2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate

Carbon disulfide (1.36 mL, 22.6 mmol) was added to a solution of methyl3-amino-4-(aminomethyl)benzoate (2.0 g, 11.3 mmol) in pyridine (10 mL)and the resultant reaction mixture was stirred at 60° C. overnight.After cooling, water was added to the reaction mixture. The solid formedwas filtrated to afford methyl2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (2.2 g) which wascarried to the next step without further purification.

Step 1e. Synthesis of methyl2-(methylthio)-3,4-dihydroquinazoline-7-carboxylate

To a suspension of methyl2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (110 mg, 0.5 mmol)in anhydrous EtOH (5 mL) was added MeI (0.125 mL, 2 mmol). The reactionmixture was stirred at reflux for 1 hr. After cooling, the solid wasisolated by filtration to afford methyl2-(methylthio)-3,4-dihydroquinazoline-7-carboxylate (100 mg).

Step 1f. Synthesis of methyl2-(2,4-dimethoxybenzylamino)-3,4-dihydroquinazoline-7-carboxylate

Methyl 2-(methylthio)-3,4-dihydroquinazoline-7-carboxylate (1.30 g, 4.2mmol) was dissolved in tBuOH (10 mL) and(2,4-dimethoxyphenyl)methanamine (2.8 g, 16.8 mmol) was added. Thereaction mixture was heated at reflux overnight. After cooling, thesolid was filtrated to afford methyl2-(2,4-dimethoxybenzylamino)-3,4-dihydroquinazoline-7-carboxylate (1.0g) as brown solid.

Step 1g. Synthesis of2-(2,4-dimethoxybenzylamino)-3,4-dihydroquinazoline-7-carboxylic acid

Hydrolysis of the ester to acid was prepared following the proceduredescribed in step 1e of Example 14.

Step 2. Synthesis oftert-butyl3-((2R)-2-(2-(2,4-dimethoxybenzylamino)-3,4-dihydroquinazoline-7-carboxamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and2-(2,4-dimethoxybenzylamino)-3,4-dihydroquinazoline-7-carboxylic acidfollowing the procedure described in step 1 of Example 3. The crudeproduct was purified by flash chromatography on silica gel(Hexane/EtOAc, 2:1 to 1:4). ESI-MS m/z 753.1 (MH)⁺.

Step 3. Synthesis of(R)-3-(2-amino-3,4-dihydroquinazoline-7-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from tert-butyl3-((2R)-2-(3,4-bis((tert-butoxycarbonylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 381 (MH)⁺.

Example 16:(R)-3-(2-carbamimidoylisoindoline-5-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-3-(2-carbamimidoylisoindoline-5-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

To (R)-3-(2-borono-2-(isoindoline-5-carboxamido)ethyl)-2-hydroxybenzoicacid from Example 9 (15 mg) in MeOH (2 mL) was added tert-butyl(1H-pyrazol-1-yl)methanediylidenedicarbamate (15 mg) and stirred for 4hr. The solvent was removed in vacuo. The residue was dissolved in 4NHCl in dioxane (2 mL) and stirred for 2 hr. The solvent was removed invacuo and the crude product was purified by reverse phase preparativeHPLC and dried using lyophilization. ESI-MS m/z 395 (MH)⁺.

Example 17:(R)-3-(3-amino-4,5-dihydro-1H-benzo[e][1,3]diazepine-7-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-3-(3-amino-4,5-dihydro-1H-benzo[e][1,3]diazepine-7-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

To(R)-3-(2-(3,4-bis(aminomethyl)benzamido)-2-boronoethyl)-2-hydroxybenzoicacid (10 mg) in DMF (1 mL) was added BrCN (10 mg) and the reaction wasstirred for 5 hr. The crude product was purified by reverse phasepreparative HPLC and dried using lyophilization. ESI-MS m/z 395 (MH)⁺.

Example 18:(R)-3-(3-amino-4-((dimethylamino)methyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1 Synthesis of 4-((dimethylamino)methyl)-3-nitrobenzoic acid Step1a. Synthesis of methyl 4-(bromomethyl)-3-nitrobenzoate

Prepared from methyl 4-methyl-3-nitrobenzoate following the proceduredescribed in step 1 in Example 14.

Step 1b. Synthesis methyl 4-((dimethylamino)methyl)-3-nitrobenzoate

To methyl 4-(bromomethyl)-3-nitrobenzoate (100 mg) in THF (5 mL) wasadded dimethyl amine (2 mL, 2 M in THF) and the resulting reactionmixture was stirred at room temperature overnight. The solvent was thenremoved to afford methyl 4-((dimethylamino)methyl)-3-nitrobenzoate whichwas carried on to the next step without further purification.

Step 1s. Synthesis of 4-((dimethylamino)methyl)-3-nitrobenzoic acid

Prepared from methyl 4-((dimethylamino)methyl)-3-nitrobenzoate using theprocedure described in step 1e. of Example 14.

Step 2. Synthesis of tert-butyl3-((2R)-2-(4-((dimethylamino)methyl)-3-nitrobenzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 4-((dimethylamino)methyl)-3-nitrobenzoic acidfollowing the procedure described in step 1 of Example 3. The crudeproduct was purified by flash chromatography on silica gel(Hexane/EtOAc, 2:1 to 1:2).

Step 3. Synthesis of tert-butyl3-((2R)-2-(3-amino-4-((dimethylamino)methyl)benzamido)-2-(3a,6,6-trimethylhexahydrobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-2-methoxybenzoate

Prepared following the procedure described in step 2 in Example 9.ESI-MS m/z 606.1 (MH)⁺.

Step 4. Synthesis of(R)-3-(3-amino-4-((dimethylamino)methyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared fromtert-butyl3-((2R)-2-(3-amino-4-((dimethylamino)methyl)benzamido)-2-(3a,6,6-trimethylhexahydrobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 384 (MH)⁺.

Example 19:(R)-3-(3,4-bis((methylamino)methyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of3,4-bis((tert-butoxycarbonyl(methyl)amino)methyl)benzoic acid

To 3,4-bis((tert-butoxycarbonylamino)methyl)benzoic acid (380 mg, 1mmol) in THF (5 mL) was added NaH (200 mg, 60%). After stirring at roomtemperature for 20 min, MeI (4 eq) was added and the resultant solutionstirred at room temperature overnight. Water was added and the aqueousphase extracted with EtOAc. The organic phase was washed with brine,dried and concentrated in vacuo to afford methyl3,4-bis((tert-butoxycarbonylamino)methyl)benzoate (368 mg). The esterwas hydrolyzed following the procedure described in step 1e of Example14 to afford 3,4-bis((tert-butoxycarbonyl(methyl)amino)methyl)benzoicacid (300 mg).

Step 2. Synthesis of tert-butyl3-((2R)-2-(3,4-bis((tert-butoxycarbonyl(methyl)amino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and3,4-bis((tert-butoxycarbonyl(methyl)amino)methyl)benzoic acid followingthe procedure described in step 1 of Example 3. The crude product waspurified by flash chromatography on silica gel (Hexane/EtOAc, 2:1 to1:2). ESI-MS m/z 820.1 (MH)⁺.

Step 3. Synthesis of(R)-3-(3,4-bis((methylamino)methyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from tert-butyl 3-((2R)-2-(3,4-bis((tert-butoxycarbonyl(methyl)amino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 398 (MH)⁺.

Example 20:(R)-3-(2-(3,4-bis(aminomethyl)phenyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of 2-(3,4-bis(aminomethyl)phenyl)acetic acid

2-(3,4-dimethylphenyl)acetic acid methyl ester (1 g), NBS (2.2 g) andAIBN (0.1 g) in CCl₄ (10 mL) were heated at reflux for 10 hr. Aftercooling and filtration, the solvent was removed and the residue wasdissolved in DCM and the organic phase washed with water and aqueoussaturated NaHCO₃ solution. The organic phase was dried over Na₂SO₄ andconcentrated in vacuo. The product (1.90 g) was used directly to thenext step without further purification.

To methyl 2-(3,4-bis(bromomethyl)phenyl)acetate (1.9 g) in EtOH/THF/H₂O(70 mL, 4:2:1) was added NaN₃ (1.09 g, 17 mmol) and the resultantreaction mixture stirred at room temperature overnight. The aqueouslayer was extracted with EtOAc (100 mL×3). The organic phases werecombined, washed with brine, dried and concentrated. The residue wasused directly to the next step without further purification.

The crude material from the above step was dissolved in MeOH (150 mL)and Pd on C (10%, 100 mg) was added. The reaction mixture washydrogenated using Parr at 60 psi for 4 hr. The reaction mixture wasfiltrated over Celite and concentrated in vacuo to afford the productwhich was used directly in the next step without further purification.

To methyl 3,4-bis(aminomethyl)benzoate from the above step (2.6 g) inDCM (100 mL) was added TEA (5 mL) and di-tert-butyl dicarbonate (4.5 g).The resultant reaction mixture was stirred at room temperatureovernight. The organic phase was washed with 1N HCl, brine, dried andconcentrated in vacuo. The residue was purified over silica gel toafford the product (1.1 g)

The methyl 2-(3,4-bis((tert-butoxycarbonylamino)methyl)phenyl)acetate(1.1 g,) was dissolved in a mixture of MeOH/THF (50 mL, 2:1). 1N NaOH(10 mmol, 10 mL) was added and the reaction mixture was stirred at roomtemperature overnight. 1N HCl was added to adjust the pH of the reactionto ˜3. The aqueous was extracted with EtOAc. The organic phase waswashed with 1N HCl, brine, dried and concentrated in vacuo to afford theproduct (0.38 g) as yellow solid.

Step 2. Synthesis oftert-butyl3-((2R)-2-(2-(3,4-bis((tert-butoxycarbonylamino)methyl)phenyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 2-(3,4-bis(aminomethyl)phenyl)acetic acidfollowing the procedure described in step 1 of Example 3. The crudeproduct was purified by flash chromatography on silica gel(Hexane/EtOAc, 2:1 to 1:2). ESI-MS m/z 806.1 (MH)⁺.

Step 3. Synthesis of(R)-3-(2-(3,4-bis(aminomethyl)phenyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from tert-butyl3-((2R)-2-(2-(3,4-bis((tert-butoxycarbonylamino)methyl)phenyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 384 (MH)⁺.

Example 21:(R)-3-(3-((S)-2,3-diaminopropanamido)-4-((dimethylamino)methyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis oftert-butyl3-((2R)-2-(3-((S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanamido)-4-((dimethylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

To tert-butyl3-((2R)-2-(3-amino-4-((dimethylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoatefrom step 3 in Example 18 (130 mg, 0.22 mol) and(S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanoicacid (85 mg, 0.25 mol) in DCM/DMF (4 mL, 1/1) was added NMM (1.2 eq)followed by HATU (114 mg, 0.3 mol). The reaction mixture was stirredovernight at rt. Water was added and the aqueous phase extracted withEtOAc. The organic phase was washed with 1N HCl, sat. NaHCO₃, brine,dried and concentrated in vacuo to afford the product (0.130 g) as abrown oil. ESI-MS m/z 926.1 (MH)⁺.

Step 2. Synthesis oftert-butyl3-((2R)-2-(3-((S)-2-amino-3-(tert-butoxycarbonylamino)propanamido)-4-((dimethylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

To tert-butyl3-((2R)-2-(3-((S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanamido)-4-((dimethylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate(130 mg) in MeOH (20 mL was added 10% Pd/C (20 mg). The reaction mixturewas stirred under H2 balloon for 6 hr. The catalyst was removed byfiltration and MeOH removed under reduced pressure to afford the product(90 mg) which was carried on to the next step.

Step 3. Synthesis of(R)-3-(3-((S)-2,3-diaminopropanamido)-4-((dimethylamino)methyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared fromtert-butyl3-((2R)-2-(3-((S)-2-amino-3-(tert-butoxycarbonylamino)propanamido)-4-((dimethylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 470 (MH)⁺.

Example 22:(R)-3-(3-((S)-2,3-diaminopropanamido)-4-methylbenzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-3-(3-((S)-2,3-diaminopropanamido)-4-methylbenzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

3-((R)-2-borono-2-(3-((S)-2,3-diaminopropanamido)-4-methylbenzamido)ethyl)-2-hydroxybenzoicacid was obtained as a byproduct from Example 21. ESI-MS m/z 427 (MH)⁺.

Example 23:(R)-3-(3-amino-4-methylbenzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-3-(3-amino-4-methylbenzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

(R)-3-(2-(3-amino-4-methylbenzamido)-2-boronoethyl)-2-hydroxybenzoicacid was obtained as a byproduct from Example 18. ESI-MS m/z 341 (MH)⁺.

Example 24:(R)-2-hydroxy-3-(4-(pyridin-2-yl)benzamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

(R)-2-hydroxy-3-(4-(pyridin-2-yl)benzamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid was prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 4-(pyridin-2-yl)benzoic acid following theprocedure described in step 1 and step 2 of Example 3. The final productwas purified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 389 (MH)⁺.

Example 25:(R)-3-(3,4-bis(guanidinomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

(R)-3-(3,4-bis(guanidinomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid was prepared from(R)-3-(2-(3,4-bis(aminomethyl)benzamido)-2-boronoethyl)-2-hydroxybenzoicacid (Example 14) using the procedure described in Example 16. ESI-MSm/z 454 (MH)⁺.

Example 26:(R)-2-hydroxy-3-(1H-indole-5-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of3-[2-[(1H-Indole-5-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-2-methoxy-benzoicacid tert-butyl ester

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and indole-5-carboxylic acid following theprocedure described in step 1 of Example 3. The crude product waspurified by flash chromatography on silica gel (EtOAc:Hexane, 0-100%).ESI-MS m/z 573.5 (MH)⁺.

Step 2. Synthesis of2-Hydroxy-3-[(1H-indole-5-carbonyl)-amino]-3,4-dihydro-2H-1-oxa-2-bora-naphthalene-8-carboxylicacid

Prepared from3-[2-[(1H-Indole-5-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-2-methoxy-benzoicacid tert-butyl ester and BCl₃ following the procedure described in Step2 of Example 3. The crude product was purified by reverse phasepreparative HPLC and dried using lyophilization. ESI-MS m/z 351.0 (MH)⁺.

Example 27:(R)-2-hydroxy-3-(4-(pyridin-4-yl)benzamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of2-Methoxy-3-[2-(4-pyridin-4-yl-benzoylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-benzoicacid tert-butyl ester

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 4-(4-pyridyl)benzoic acid following theprocedure described in step 1 of Example 3. The crude product waspurified by flash chromatography on silica gel (EtOAc:Hexane, 0-100%).ESI-MS m/z 611.5 (MH)⁺.

Step 2. Synthesis of2-Hydroxy-3-(4-pyridin-4-yl-benzoylamino)-3,4-dihydro-2H-1-oxa-2-bora-naphthalene-8-carboxylicacid

Prepared from2-Methoxy-3-[2-(4-pyridin-4-yl-benzoylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-benzoicacid tert-butyl ester and BCl₃ following the procedure described in Step2 of Example 3. The crude product was purified by reverse phasepreparative HPLC and dried using lyophilization. ESI-MS m/z 389.0 (MH)⁺.

Example 28:(R)-2-hydroxy-3-(quinoline-6-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of2-Methoxy-3-[2-[(quinoline-6-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-benzoicacid tert-butyl ester

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 6-quinolinecarboxylic acid following theprocedure described in step 1 of Example 3. The crude product waspurified by flash chromatography on silica gel (EtOAc:Hexane, 0-100%).ESI-MS m/z 585.5 (MH)⁺.

Step 2. Synthesis of2-Hydroxy-3-[(quinoline-6-carbonyl)-amino]-3,4-dihydro-2H-1-oxa-2-bora-naphthalene-8-carboxylicacid

Prepared from2-Methoxy-3-[2-[(quinoline-6-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-benzoicacid tert-butyl ester and BCl₃ following the procedure described in Step2 of Example 3. The crude product was purified by reverse phasepreparative HPLC and dried using lyophilization. ESI-MS m/z 363.0 (MH)⁺.

Example 29:(R)-2-hydroxy-3-(quinoxaline-6-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of2-Methoxy-3-[2-[(quinoxaline-6-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-benzoicacid tert-butyl ester

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and quinoxaline-6-carboxylic acid following theprocedure described in step 1 of Example 3. The crude product waspurified by flash chromatography on silica gel (EtOAc:Hexane, 0-100%).ESI-MS m/z 586.5 (MH)⁺.

Step 2. Synthesis of2-Hydroxy-3-[(quinoxaline-6-carbonyl)-amino]-3,4-dihydro-2H-1-oxa-2-bora-naphthalene-8-carboxylicacid

Prepared from2-Methoxy-3-[2-[(quinoxaline-6-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-benzoicacid tert-butyl ester and BCl₃ following the procedure described in Step2 of Example 3. The crude product was purified by reverse phasepreparative HPLC and dried using lyophilization. ESI-MS m/z 364.0 (MH)⁺.

Example 30:(R)-2-hydroxy-3-(1H-indole-6-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-2-Hydroxy-3-[(M-indole-6-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and indole-6-carboxylic acid following theprocedure described in step 1 and step 2 of Example 3. The final productwas purified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 351 (MH)⁺.

Example 31:(R)-2-hydroxy-3-(1H-indole-7-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-2-hydroxy-3-(1H-indole-7-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and indole-7-carboxylic acid following theprocedure described in step 1 and step 2 of Example 3. The final productwas purified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 351 (MH)⁺.

Example 32:(R)-2-Hydroxy-3-[(1H-indole-4-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-2-Hydroxy-3-[(M-indole-4-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and indole-4-carboxylic acid following theprocedure described in step 1 and step 2 of Example 3. The final productwas purified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 351 (MH)⁺.

Example 33:(R)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 5-carboxyoxindole following the proceduredescribed in step 1 and step 2 of Example 3. The final product waspurified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 367 (MH)⁺.

Example 34:(R)-3-[(3H-Benzoimidazole-5-carbonyl)-amino]-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-3-[(3H-Benzoimidazole-5-carbonyl)-amino]-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 1H-benzimidazole-6-carboxylic acid followingthe procedure described in step 1 and step 2 of Example 3. The finalproduct was purified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 352 (MH)⁺.

Example 35:(R)-2-Hydroxy-3-[(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-2-Hydroxy-3-[(M-pyrrolo[2,3-b]pyridine-5-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acidfollowing the procedure described in step 1 and step 2 of Example 3. Thefinal product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 352 (MH)⁺.

Example 36:(3R)-2-hydroxy-3-[(2-isoindolin-5-ylacetyl)amino]-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Step 1. Synthesis of 4-bromo-1,2-bis(bromomethyl)benzene

To a solution of 4-bromo-1,2-dimethyl-benzene (3.7 g, 20 mmol) in carbontetrachloride (40 mL) was added N-bromo-succinamide (7.83 g, 44 mmol).To this mixture was added azo-bis-isobutyronitrile (AIBN, 150 mg). Theresulting suspension was warmed to reflux and stirred at thistemperature for 3 hr. A further portion of AIBN was added (75 mg) andstirring continued for 15 hr. The reaction mixture was cooled to roomtemperature, filtered and the filtrate concentrated under vacuum. Theresidue was purified by silica chromatography (50 g silica eluted withhexane) to give a semi solid product. This material is triturated withhexane and filtered to give the title compound as a white solid.

Step 2. Synthesis of 5-bromo-2-(p-tolylsulfonyl)isoindoline

To a suspension of sodium hydride (440 mg, 60% dispersion in mineraloil, 11 mmol) in N,N-dimethylacetamide (24 mL) was added, dropwise, asolution of p-toluenesulfonamide (1.45 g, 8.5 mmol) inN,N-dimethylacetamide (8 mL) over about 5 min. The frothy solution wasstirred for 1 hr at room temperature then heated to 60° C. and stirredat this temperature for 0.5 hr. To this mixture was added, dropwise asolution of 4-bromo-1,2-bis(bromomethyl)benzene (2.9 g 8.4 mmol) inN,N-dimethylacetamide (6 mL). The resulting mixture was stirred for 1 hrthen cooled to room temperature and stirred for 17 hr. The mixture wasthen diluted with ether, washed with water (2×) then brine, dried oversodium sulfate and concentrated. The residue was triturated with ethylacetate and filtered to give the title compound as a white solid.

Step 3. Synthesis of 5-bromoisoindoline

To a solution of aqueous hydrobromic acid (16 mL, 48% solution inwater), propionic acid (2.8 mL) and phenol (2 g) was added5-bromo-2-(p-tolylsulfonyl)isoindoline (2.4 g, 6.8 mmol). The resultingmixture was heated to reflux and stirred at this temperature for 10 hrthen cooled to room temperature. This mixture was diluted with water (20mL) and extracted with ether (2×50 mL). The aqueous extract was broughtto pH 14 with 5M sodium hydroxide solution. This solution was extractedwith ether (3×). The ether extract is washed with brine, dried overmagnesium sulfate, and concentrated to give the title compound as anoil.

Step 4. Synthesis of benzyl 5-bromoisoindoline-2-carboxylate

To a cooled solution of 5-bromoisoindoline (1.1 g, 5.5 mmol) indichloromethane (15 mL) was added N,N-diisopropylethylamine (1.16 mL,6.6 mmol) followed by benzyl chloroformate (942 μL, 6.6 mmol). The coldbath was removed and stirring continued for 2 hr. The reaction mixturewas then diluted with dichloromethane, washed with water, dried overmagnesium sulfate and concentrated under vacuum. The residue waspurified by silica chromatography (25 g silica eluted with 0-50% ethylacetate in hexane) to give the title compound as a white solid.

Step 5. Synthesis of benzyl 5-allylisoindoline-2-carboxylate

To a mixture of benzyl 5-bromoisoindoline-2-carboxylate (332 mg, 1mmol), tetrakistriphenylphosphine palladium (0) (80 mg, 0.07 mmol), andcesium fluoride (604 mg, 4 mmol) was added THF (7 mL). The system wasdegassed and flushed with argon. To this mixture was added allyl boronicacid pinacol ester (285 μL, 1.5 mmol). The resulting mixture was heatedto 72° C. and stirred at this temperature for 4 hr then cooled to roomtemperature. The mixture was diluted with ethyl acetate, washed withbrine, dried over magnesium sulfate and concentrated under vacuum. Theresidue was purified by silica chromatography (25 g silica eluted with3-40% ethyl acetate in hexane) to give the title compound as a whitesolid.

Step 6. Synthesis of benzyl5-(2,3-dihydroxypropyl)isoindoline-2-carboxylate

To a suspension of benzyl 5-allylisoindoline-2-carboxylate (294 mg, 1mmol) in tert-butanol (2.5 mL) and water (2.5 mL) was addedN-methylmorpholine-N-oxide (257 mg, 2.2 mmol) followed by osmiumtetroxide solution (0.1 mL of 4% wt in water). The resulting mixture wasstirred for 3 hr (during which time the mixture becomes homogeneous).This solution was diluted with ethyl acetate, washed with saturatedsodium thiosulfate solution then brine, dried over magnesium sulfate andconcentrated under vacuum. The residue was purified by silicachromatography (25 g silica eluted with 3-40% ethyl acetate in hexane)to give the title compound as a white solid.

Step 7. Synthesis of benzyl 5-(2-oxoethyl)isoindoline-2-carboxylate

To a solution of benzyl 5-(2,3-dihydroxypropyl)isoindoline-2-carboxylate(327 mg, 1 mmol) in THF (7 mL) and water (7 mL) was added sodiumperiodate (426 mg, 2 mmol). The resulting mixture was stirred for 20 mindiluted with ethyl acetate, washed with water and brine, dried overmagnesium sulfate and concentrated to give the title compound a whitesolid. This material is used without further purification.

Step 8. Synthesis of 2-(2-benzyloxycarbonylisoindolin-5-yl)acetic acid

To a solution of benzyl 5-(2-oxoethyl)isoindoline-2-carboxylate (290 mg,1 mmol) in tert-butanol (10 mL) was added 2,3-dimethyl-but-2-ene (1.1mL). To this mixture was added a solution comprising sodiumdihydrogenphosphate hydrate (1.08 g, 8 mmol) and sodium chlorite (1.08g, 9.5 mmol tech grade). This mixture was stirred for 20 min dilutedwith ethyl acetate, washed with brine, dried over magnesium sulfate andconcentrated under vacuum. The residue was purified by silicachromatography (25 g silica eluted with 3-20% methanol indichloromethane) to give the title compound as a white solid.

Step 9. Synthesis of[(1S)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-chloro-ethyl]boronicacid (+) pinanediol ester

Method 1: To a cooled (−100° C. external temperature) solution ofdichloromethane (2.27 mL, 35 mmol) in THF (44 mL) was added, dropwisedown the side of the flask, BuLi (8.88 mL, 2.5 M in hexanes, 22 mmol)over 45 min. After approx. 80% of the BuLi is added, a white precipitateforms. On complete addition, the reaction mixture was stirred 30 min. Tothis mixture was added, dropwise down the side of the flask,2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester (8.0 g, 20 mmol) in THF (20 mL) over approximately30 min. On complete addition, the resulting solution was stirred for 5min. To this solution was added ZnCl₂ (22 mL, 1M in ether) dropwise downthe side of the flask, over approximately 12 min. On complete addition,the cold bath was removed and replaced with a −10° C. bath. The reactionmixture was stirred for 1.25 hr. To this solution is added ice coldether (300 mL) and ice cold saturated aqueous NH₄Cl (125 mL). Theorganic phase was washed with brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicachromatography (120 g silica eluted with 2-20% ethyl acetate in hexane)to give the title compound as a colorless oil. This material slowlycrystallizes at −10° C.

Method 2:2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester (2.0 g, 5 mmol) and dichloromethane (1.6 mL, 25mmol) in THF (20 mL) was stirred at −60° C. for 30 min. To this solutionwas added LDA (6.5 mmol, 2 M solution from Aldrich) over a period of 10min. The resulting reaction mixture is stirred at −60° C. for 20 min.ZnCl₂ (8.75 mmol, 1M solution in ether) was added at −60° C. slowly. Thereaction mixture was stirred at −50 to −60° C. for 30 min. Thisresulting mixture was warmed up to 0° C. over a period of 1 h, at whichtime, 10% H₂SO₄ solution (10 mL) was added and the reaction mixturestirred for 10 min. After phase separation, the organic phase was washedwith water and brine. The organic phase was then dried and concentratedin vacuo. The residue was then purified by flash silica chromatography(EtOAc/Hexane: 4/1) to give the title compound.

Step 10. Synthesis of tert-butyl3-((2R)-2-(2-benzyloxycarbonylisoindolin-5-yl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

To a cooled (−78° C.) solution of[(1S)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-chloro-ethyl]boronicacid (+) pinanediol ester (450 mg, 1 mmol) in THF (3 mL) was addedlithium bis-trimethylsilylamide (1.0 mL, 1M in THF) dropwise. Oncomplete addition, the cold bath was removed and stirring continued for19 hr to give a solution of[(1R)-1-[bis(trimethylsilyl)amino]-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)ethyl]boronicacid (+) pinanediol ester, approximately 0.25M in THF. This solution wasused directly in the next operation.

In a separate flask: To a mixture of2-(2-benzyloxycarbonylisoindolin-5-yl)-acetic acid (311 mg, 1 mmol) andHATU (418 mg, 1.1 mmol) was added DMA (3 mL) followed byN-methylmorpholine (122 μL, 1.1 mmol). The resulting solution wasstirred for 1.5 hr then the solution of[(1R)-1-[bis(trimethylsilyl)amino]-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)ethyl]boronicacid (+) pinanediol in THF (prepared above) was added. This mixture wasstirred for 4 h, diluted with ethyl acetate, washed with water andbrine, dried over magnesium sulfate and concentrated. The residue waspurified by silica chromatography (10 g silica, eluted with 40-100%ethyl acetate in hexanes) to give the title compound as a foam. ESI-MSm/z 745 (M+Na)⁺.

Step 11. Synthesis oftert-butyl3-((2R)-2-(isoindolin-5-yl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

To a solution of tert-butyl3-((2R)-2-(2-benzyloxycarbonylisoindolin-5-yl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate(460 mg, 0.63 mmol) in methanol (4 mL) was added palladium on carbon (46mg, 10% palladium by weight). This mixture was flushed with hydrogen gasand stirred under this atmosphere for 2.5 hr. The mixture was flushedwith nitrogen, diluted with dichloromethane and filtered. The filtratewas concentrated to give the title compound as a tan oil that is usedwithout further purification.

Step 12. Synthesis of(3R)-2-hydroxy-3-[(2-isoindolin-5-ylacetyl)amino]-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

To a solution of tert-butyl3-((2R)-2-(isoindolin-5-yl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate(150 mg, 0.25 mmol) in dioxane (2 mL) was added HCl (2 mL, 3M aqueous).The resulting solution was heated to reflux and stirred at thistemperature for 2.5 hr. The resulting mixture was cooled to roomtemperature and extracted with ether (2×). The aqueous extractconcentrated to about 1 volume and the residue was purified by reversephase HPLC. Pure fractions are concentrated by lyophilization to givethe title compound as a white solid. ESI-MS m/z 367 (MH)⁺.

Example 37:(3R)-3-[[2-(2-carbamimidoylisoindolin-5-yl)acetyl]amino]-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Step 1. Synthesis oftert-butyl(3R)-3-[[2-[2-[(Z)—N,N′-bis(tert-butoxycarbonyl)carbamimidoyl]isoindolin-5-yl]acetyl]amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

To a solution of tert-butyl3-((2R)-2-(isoindolin-5-yl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate(190 mg, 0.31 mmol) in methanol (3 mL) was addedbis-BOC-(pyrazol-1-yl)-carboxamidine (124 mg, 0.4 mmol). The resultingsolution was stirred for 3 hr then concentrated under reduced pressure.The residue was purified by silica chromatography (10 g silica elutedwith 20-100% ethyl acetate in hexane) to give the title compound.

Step 2. Synthesis of(3R)-3-[[2-(2-carbamimidoylisoindolin-5-yl)acetyl]amino]-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Prepared from tert-butyl(3R)-3-[[2-[2-[(Z)—N,N′-bis(tert-butoxycarbonyl)carbamimidoyl]isoindolin-5-yl]acetyl]amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 1. Thecrude product was purified by reverse phase HPLC. Pure fractions areconcentrated by lyophilization to give the title compound as a whitesolid. ESI-MS m/z 409 (MH)⁺.

Example 38:(R)-3-(2-(3,4-dihydroxyphenyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis oftert-butyl3-((2R)-2-(2-(3,4-dihydroxyphenyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 2-(3,4-dihydroxyphenyl)acetic acid followingthe procedure described in step 1 of Example 1. The crude product waspurified by flash chromatography on silica gel (Hexane/EtOAc 4:1 to1:2). ESI-MS m/z 580.1 (MH)⁺.

Step 2. Synthesis of(R)-3-(2-(3,4-dihydroxyphenyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

tert-Butyl3-((2R)-2-(2-(3,4-dihydroxyphenyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate(200 mg) was mixed with 3 ml of 3N HCl and the reaction mixture washeated at reflux for 1 hr. The reaction solution was cooled and washedwith dichloromethane three times. The crude product in the aqueous phasewas purified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 358 (MH)⁺.

Example 39:(R)-3-(3,4-dihydroxybenzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of 3,4-diacetoxybenzoic acid

To a solution of 3,4-dihydroxybenzoic acid (0.84 g) and DMAP (80 mg) inpyridine (5 mL) at 0° C. was added acetic anhydride (1.2 mL). Thereaction mixture was stirred overnight. The reaction mixture was thenpoured over crushed ice. The solution was acidified (pH<2) and extractedwith EtOAc. The combined extracts were dried over Na₂SO₄ andconcentrated in vacuo to afford the product (0.9 g).

Step 2. Synthesis of(R)-3-(3,4-dihydroxybenzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 3,4-diacetoxybenzoic acid (step 1) followingthe procedure described in step 1 and step 2 of Example 39. The crudeproduct was purified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 344 (MH)⁺.

Example 40:(R)-3-(4-(2-aminoethoxy)-3-hydroxybenzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis oftert-butyl3-((2R)-2-(3-acetoxy-4-hydroxybenzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

The titled product was obtained as a side product in step 2 of Example39 during chromatography.

Step 2. Synthesis oftert-butyl3-((2R)-2-(3-acetoxy-4-(2-aminoethoxy)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Totert-butyl3-((2R)-2-(3-acetoxy-4-hydroxybenzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate(100 mg from step 1) in DMF (3 mL) was added K₂CO₃ (100 mg) followed bytert-butyl2-bromoethylcarbamate (100 mg). The resulting reaction mixturewas stirred at room temperature overnight. Water was added to thereaction mixture and extracted with EtOAc three times. The combinedorganic phases were dried and concentrated to afford the product whichwas carried on to the next step without further purification.

Step 3. Synthesis of(R)-3-(4-(2-aminoethoxy)-3-hydroxybenzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from tert-butyl3-((2R)-2-(3-acetoxy-4-(2-aminoethoxy)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoatefollowing the procedure described in step 2 of Example 38. The crudeproduct was purified by reverse phase preparative HPLC and dried usinglyophilization. ESI-MS m/z 387 (MH)⁺.

Example 41:(R)-3-{[1-(2-Amino-ethyl)-1H-indole-6-carbonyl]-amino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of 1H-Indole-6-carboxylic acid methyl ester

Iodomethane (0.75 mL, 12.0 mmol) was added to a suspension ofindole-6-carboxylic acid (1.68 g, 10.5 mmol) and potassium carbonate(2.16 g, 15.7 mmol) in DMF (30 mL) under argon. The reaction was stirredat room temperature for 19 hr. The reaction was quenched with sat. NH₄Cand extracted with ethyl acetate (2×). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude product was purified by flash chromatography on silica gel (0-60%EtOAc:Hexane). ESI-MS m/z 176 (MH)⁺.

Step 2. Synthesis of1-(2-tert-Butoxycarbonylamino-ethyl)-1H-indole-6-carboxylic acid methylester

A solution of 1H-Indole-6-carboxylic acid methyl ester (0.503 g, 2.87mmol) and DMF (9.0 mL) under argon was cooled to 0° C. for 10 min.Sodium hydride (˜48%, 0.190 g, 3.80 mmol) was added and reaction warmedto room temperature for 30 min. 2-(Boc-amino)ethyl bromide (0.787 g,3.52 mmol) was added and the reaction stirred for 17 hr. The reactionwas quenched with H₂O and extracted with ethyl acetate (3×). Thecombined organic layers were washed with H₂O and brine, dried overNa₂SO₄, filtered, and concentrated. The crude product was purified byflash chromatography on silica gel (0-50% EtOAc:Hexane). ESI-MS m/z 319(MH)⁺.

Step 3. Synthesis of1-(2-tert-Butoxycarbonylamino-ethyl)-1H-indole-6-carboxylic acid

Sodium hydroxide (1N, 6.0 mL, 6.00 mmol) was added to a solution of1-(2-tert-Butoxycarbonylamino-ethyl)-1H-indole-6-carboxylic acid methylester (0.501 g, 1.57 mmol) in methanol (12 mL) and THF (4.0 mL). Thereaction was stirred at room temperature for 68 hr. The reaction wasconcentrated in vacuo. The aqueous residue was acidified to pH 1 with 1NHCl and extracted with ethyl acetate (3×). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated. The crude productwas carried forward without purification. ESI-MS m/z 327 (M+Na)⁺.

Step 4. Synthesis of(R)-3-{[1-(2-Amino-ethyl)-1H-indole-6-carbonyl]-amino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and1-(2-tert-Butoxycarbonylamino-ethyl)-1H-indole-6-carboxylic acidfollowing the procedure described in step 1 and step 2 of Example 3. Thefinal product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 394 (MH)⁺.

Example 42:(R)-3-{[1-(2-Amino-ethyl)-1H-indole-4-carbonyl]-amino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-3-{[1-(2-Amino-ethyl)-1H-indole-4-carbonyl]-amino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from indole-4-carboxylic acid following the procedure describedin steps 1 through 4 of Example 40. The final product was purified byreverse phase preparative HPLC and dried using lyophilization. ESI-MSm/z 394 (MH)⁺.

Example 43:(R)-2-Hydroxy-3-[(1-methyl-1H-indole-6-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of 1-Methyl-1H-indole-6-carboxylic acid methyl ester

Iodomethane (2.3 mL, 36.9 mmol) was added to a suspension ofindole-6-carboxylic acid (1.55 g, 9.62 mmol) and potassium carbonate(1.98 g, 14.3 mmol) in DMF (32 mL) under argon. The reaction was stirredat room temperature for 24 hr. The reaction was quenched with sat. NH₄Cand extracted with ethyl acetate (2×). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude product was purified by flash chromatography on silica gel (0-60%EtOAc:Hexane). ESI-MS m/z 190 (MH)⁺.

Step 2. Synthesis of(R)-2-Hydroxy-3-[(1-methyl-1H-indole-6-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from 1-Methyl-1H-indole-6-carboxylic acid methyl esterfollowing the procedure described in steps 3 and 4 of Example 40. Thefinal product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 365 (MH)⁺.

Example 44:(R)-3-(3,5-bis(aminomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of 3,5-bis((tert-butoxycarbonylamino)methyl)benzoicacid

Prepared from 3,5-dimethylbenzoic acid following the proceduresdescribed in step 1a-1e, Example 14.

Step 2. Synthesis oftert-butyl3-((2R)-2-(3,4-bis((tert-butoxycarbonylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Prepared from[(1S)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-chloro-ethyl]boronicacid (+) pinanediol ester and3,5-bis((tert-butoxycarbonylamino)methyl)benzoic acid following theprocedure described in step 10 of Example 36. The crude product waspurified by flash chromatography on silica gel (Hexane/EtOAc, 2:1 to1:2). ESI-MS m/z 792.1 (MH)⁺.

Step 3. Synthesis of(R)-3-(3,5-bis(aminomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared fromtert-butyl3-((2R)-2-(3,5-bis((tert-butoxycarbonylamino)methyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 370 (MH)⁺.

Example 45:(R)-3-(3,5-bis(guanidinomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-3-(3,5-bis(guanidinomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

(R)-3-(3,5-bis(guanidinomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid was prepared from(R)-3-(2-(3,5-bis(aminomethyl)benzamido)-2-boronoethyl)-2-hydroxybenzoicacid (Example 44) using the procedure described in Example 16. Theproduct was purified by reverse phase HPLC and dried usinglyophilization. ESI-MS m/z 454 (MH)⁺.

Example 46:(R)-2-Hydroxy-3-(2-1H-indol-6-yl-acetylamino)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of3-[2-(2-1H-Indol-6-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-2-methoxy-benzoicacid tert-butyl ester

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 2-(1H-indol-6-yl)acetic acid following theprocedure described in Step 1 of Example 1. The crude product waspurified by flash chromatography on silica gel (EtOAc:Hexane, 25-100%).ESI-MS m/z 587 (MH)⁺.

Step 2. Synthesis of(R)-2-Hydroxy-3-(2-1H-indol-6-yl-acetylamino)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from3-[2-(2-1H-Indol-6-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-2-methoxy-benzoicacid tert-butyl ester and BCl₃ following the procedure described in Step2 of Example 1. The crude product was purified by reverse phasepreparative HPLC and dried using lyophilization. ESI-MS m/z 365 (MH)⁺.

Example 47:(R)-2-Hydroxy-3-[4-(1H-imidazol-2-yl)-benzoylamino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of3-[2-[4-(1H-Imidazol-2-yl)-benzoylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-2-methoxy-benzoicacid tert-butyl ester

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 4-(1H-imidazol-2-yl)benzoic acid following theprocedure described in Step 1 of Example 1. The crude product waspurified by flash chromatography on silica gel (CH₃H:CH₂Cl₂, 0-15%).ESI-MS m/z 600 (MH)⁺.

Step 2. Synthesis of(R)-2-Hydroxy-3-[4-(H-imidazol-2-yl)-benzoylamino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from3-[2-[4-(1H-Imidazol-2-yl)-benzoylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-2-methoxy-benzoicacid tert-butyl ester and BCl₃ following the procedure described in Step2 of Example 1. The crude product was purified by reverse phasepreparative HPLC and dried using lyophilization. ESI-MS m/z 378 (MH)⁺.

Example 48:(R)-2-Hydroxy-3-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-acetylamino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of Di-prop-2-ynyl-carbamic acid tert-butyl ester

A mixture of N-Boc-propargylamine (2.63 g, 16.9 mmol) and DMF (35 mL)was prepared under argon and cooled to 0° C. for 20 min. Sodium hydride(60%, 0.714 g, 17.9 mmol) was added and the reaction stirred at 0° C.for 30 min. Propargyl bromide (80% in toluene, 2.7 mL, 24.2 mmol) in DMF(5 mL) was added slowly and the reaction stirred at 0° C. for 15 minthen warmed to room temperature and stirred for additional 17 hr. Thereaction mixture was quenched with water and extracted two times withEtOAc. The combined organic layers were washed with water (3×) andbrine, dried over Na₂SO₄, filtered, and concentrated. The crude productwas carried to the next reaction without purification. ESI-MS m/z 194(MH)⁺.

Step 2. Synthesis of 5-Carboxymethyl-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester

A mixture of di-prop-2-ynyl-carbamic acid tert-butyl ester (4.78 g, 24.7mmol) and ethanol (120 mL) was prepared under argon and cooled to 0° C.for 15 min. 3-Butynoic acid (3.64 g, 43.3 mmol) andtris(triphenylphosphine)rhodium (I) chloride (1.14 g, 1.23 mmol) wereadded and reaction was gradually warmed to room temperature over 1.3 hr.The reaction was then heated to 45° C. for 17 hr. The reaction wascooled to room temperature and concentrated in vacuo. The residue wasdiluted with 1N NaOH and extracted with diethyl ether (3×). The aqueouslayer was acidified to pH ˜1 with 1N HCl and extracted with EtOAc (3×).The combined EtOAc layers were dried over Na₂SO₄, filtered, andconcentrated. The crude product was purified by flash chromatography onsilica gel (EtOAc:Hexane, 5-100%). ESI-MS m/z 278 (MH)⁺.

Step 3. Synthesis of5-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethylcarbamoyl]-methyl}-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and5-carboxymethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl esterfollowing the procedure described in Step 1 of Example 1. The crudeproduct was purified by flash chromatography on silica gel(EtOAc:Hexane, 30-100%). ESI-MS m/z 689 (MH)⁺.

Step 4. Synthesis of3-[2-(2-2,3-Dihydro-1H-isoindol-5-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-2-methoxy-benzoicacid

Trifluoroacetic acid (0.60 mL, 8.08 mmol) was added to a solution of5-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethylcarbamoyl]-methyl}-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester (0.285 g, 0.414 mmol) in CH₂C12 (3.0 mL) underargon. The reaction was stirred at room temperature for 2 hr thenconcentrated in vacuo and carried to the next step without purification.ESI-MS m/z 533 (MH)⁺.

Step 5. Synthesis of2-Methoxy-3-[2-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-benzoicacid

A solution of3-[2-(2-2,3-Dihydro-1H-isoindol-5-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-2-methoxy-benzoicacid (0.110 g, 0.207 mmol), formaldehyde (37% in H₂O, 0.06 mL, 0.740mmol), and methanol (2.5 mL) was purged with argon. Palladium on carbon(10%, 0.049 g) was added, the flask evacuated, and the reaction placedunder hydrogen for 18 hr. The reaction mixture was filtered through aCelite-plugged filter frit, washed with CH₃OH and CH₂Cl₂, andconcentrated. The crude product was carried forward withoutpurification. ESI-MS m/z 547 (MH)⁺.

Step 6. Synthesis of(R)-2-Hydroxy-3-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-acetylamino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

To a mixture of2-Methoxy-3-[2-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-benzoicacid (0.113 g, 0.207 mmol) and 1,4-dioxane (2.0 mL) was added 3N HCl(1.7 mL, 5.10 mmol) and the reaction was heated at 100° C. for 1 hr. Thereaction was cooled to room temperature and extracted with diethyl ether(3×). The product remained in the aqueous layer and was purified byreverse phase preparative HPLC and dried using lyophilization. ESI-MSm/z 381 (MH)⁺.

Example 49:(R)-3-{2-[2-(2-Amino-ethyl)-2,3-dihydro-1H-isoindol-5-yl]-acetylamino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of3-[2-{2-[2-(2-tert-Butoxycarbonylamino-ethyl)-2,3-dihydro-1H-isoindol-5-yl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-2-methoxy-benzoicacid

A solution of3-[2-(2-2,3-Dihydro-1H-isoindol-5-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-2-methoxy-benzoicacid (0.110 g, 0.207 mmol) (prepared following the procedures in Steps1-4 in Example 48), N-Boc-2-aminoacetaldehyde (0.06 g, 0.427 mmol), andmethanol (2.5 mL) was purged with argon. Palladium on carbon (10%, 0.051g) was added, the flask evacuated, and the reaction placed underhydrogen for 91 hr. The reaction mixture was filtered through aCelite-plugged filter frit, washed with CH₃OH and CH₂Cl₂, andconcentrated. The crude product was carried forward withoutpurification. ESI-MS m/z 676 (MH)⁺.

Step 2. Synthesis of(R)-3-{2-[2-(2-Amino-ethyl)-2,3-dihydro-1H-isoindol-5-yl]-acetylamino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from3-[2-{2-[2-(2-tert-Butoxycarbonylamino-ethyl)-2,3-dihydro-1H-isoindol-5-yl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-2-methoxy-benzoicacid and HCl following the procedure described in Step 6 of Example 48.The crude product was purified by reverse phase preparative HPLC anddried using lyophilization. ESI-MS m/z 410 (MH)⁺.

Example 50:(3R)-3-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carbonylamino)-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Step 1. Synthesis of 5-bromo-2,3-dimethyl-pyridine

To a stirred solution of 2,3-dimethyl-pyridine (6.79 mL, 60 mmol) infuming sulfuric acid (80 mL) held at 150° C. in a round bottom flaskfitted with a water cooled reflux condenser and a calcium chloridefilled drying tube, was added, dropwise, bromine (3.1 mL, 60 mmol) over2 hr. The resulting dark red solution was stirred for 16 hr then cooledto room temperature and allowed to stand overnight. This mixture waspoured into approximately 400 g of ice. This mixture was brought to pH12 with cooling in an ice bath. The resulting mixture was extracted withether and the ether extract washed with brine, dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica chromatography (50 g silica, eluted with 2-20% ethylacetate in hexanes) to give the title compound (8.3 g) as a colorlessoil.

Step 2. Synthesis of 5-bromo-2,3-bis(bromomethyl)pyridine

To a solution of 5-bromo-2,3-dimethyl-pyridine (8.3 g, 44.6 mmol) inCCl₄ (120 mL) was added N-bromo-succinimide (16.77 g, 93.7 mmol)followed by AIBN (167 mg, 1 mmol). The resulting solution was heated to82° C. and stirred at this temperature for 2 hr. To this mixture wasadded AIBN (167 mg, 1 mmol). This mixture was stirred for a further 2 hrat 82° C. then cooled to room temperature. The solid precipitate wasremoved by filtration and the filtrate concentrated under reducedpressure. The residue was purified by silica chromatography (50 gsilica, eluted with 2-20% ethyl acetate in hexanes) to give the titlecompound as a mixture with starting material and tri-brominatedderivative.

Step 3. Synthesis of 3-bromo-6-trityl-5,7-dihydropyrrolo[3,4-b]pyridine

To a solution of 5-bromo-2,3-bis(bromomethyl)pyridine (Step 2 above, 5.6g, approximately 16.3 mmol) in DMF (40 mL) was added trityl amine (5.3g, 20.6 mmol) followed by diisopropylethylamine (8.6 mL, 49 mmol). Theresulting solution was warmed to 60° C. and stirred at this temperaturefor 2.5 hr. The mixture was then concentrated under reduced pressure andthe residue was purified by silica chromatography (50 g silica, elutedwith 10-100% dichloromethane in hexanes) to give the title compound as afoam.

Step 4. Synthesis of 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine

To a cooled (0° C.) solution of3-bromo-6-trityl-5,7-dihydropyrrolo[3,4-b]pyridine (1.57 g, 3.66 mmol)in chloroform (15 mL) and methanol (15 mL) was added trifluoroaceticacid (30 mL) over 1 min. On complete addition, the solution was stirredfor 5 min then the cold bath removed and stirring continued for 30 min.This solution was concentrated under reduced pressure and the residuetaken up in HCl (30 mL, 1M aq.). This mixture was extracted with ether(2×20 mL) then the aqueous phase basified with sodium hydroxide (5Maq.). This mixture was extracted with dichloromethane (3×20 mL). Thecombined dichloromethane extract was dried over magnesium sulfate andconcentrated under reduced pressure to give the title compound as asolid.

Step 5. Synthesis oftert-butyl3-bromo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate

To a solution of 3-bromo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (755 mg,3.79 mmol) in dichloromethane (15 mL) was added diisopropylethylamine(791 μL, 4.54 mmol) followed by di-tert-butyl dicarbonate (989 mg, 4.54mmol). The resulting solution was stirred for 1 hr then diluted withether, washed with brine, dried over magnesium sulfate and concentrated.The residue was purified by silica chromatography (25 g silica, elutedwith 5-40% ethyl acetate in hexanes) to give the title compound as asolid.

Step 6. Synthesis oftert-butyl3-allyl-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate

A mixture of tert-butyl3-bromo-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (857 mg, 2.87mmol), cesium fluoride (1.7 g, 11.5 mmol), andtetrakis-(triphenylphosphine) palladium (0) (229 mg, 0.2 mmol) in THF(15 mL) was degassed and flushed with nitrogen. To this mixture wasadded allyl-boronic acid pinacol ester (820 μL, 4.3 mmol). The resultingmixture was heated to reflux and stirred at this temperature for 2.5 hrthen cooled to room temperature, diluted with ether, washed with waterand brine, dried over magnesium sulfate and concentrated. The residuewas purified by silica chromatography (25 g silica, eluted with 5-40%ethyl acetate in hexanes) to give the title compound as a solid.

Step 7. Synthesis oftert-butyl3-(2,3-dihydroxypropyl)-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate

To a solution oftert-butyl3-allyl-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (430mg, 1.64 mmol) in tert-butanol (5 mL) and water (5 mL) was addedN-methyl-morpholine N-oxide (422 mg, 3.6 mmol) followed by osmiumtetroxide (20 μl, 4% aqueous solution). The resulting solution wasstirred for 48 hr then diluted with ether, washed with 10% sodiumthiosulphate solution and brine, dried over magnesium sulfate andconcentrated to give the title compound as a solid.

Step 8. Synthesis of6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxylicacid and2-(6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridin-3-yl)aceticacid

To a solution of tert-butyl3-(2,3-dihydroxypropyl)-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate(450 mg, 1.52 mmol) in THF (4.5 mL) and water (4.5 mL) was added sodiumperiodate (648 mg, 3 mmol). The resulting mixture was stirred for 20 minthen diluted with ethyl acetate, washed with water and brine, dried overmagnesium sulfate and concentrated. The residue was taken up intert-butanol (15 mL). To this solution was added 2,3-dimethyl-but-2-ene(1.7 mL) followed by a solution comprising sodium chlorite (1.6 g,technical grade approximately 14 mmol) and disodium hydrogen phosphatehydrate (1.6 g, 12 mmol) in water (15 mL). The resulting mixture wasstirred for 20 min then diluted with ethyl acetate, washed with waterand brine, dried over magnesium sulfate, and concentrated to give thetitle compounds (approximately 1:9 ratio) as a solid. This product wasused without further purification.

Step 9. Synthesis of[(1R)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-[(6-tert-butoxycarbonyloxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carbonyl)amino]ethyl]boronicacid (+) pinanediol ester

The title compound was prepared using essentially the same proceduredescribed in Example 36 step 10 except using6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carboxylicacid and2-(6-tert-butoxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridin-3-yl)aceticacid in place of 2-(2-benzyloxycarbonylisoindolin-5-yl)-acetic acid.

Step 10. Synthesis of(3R)-3-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carbonylamino)-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

The title compound was prepared using essentially the same proceduredescribed in Example 36, step 12 except using[(1R)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-[(6-tert-butoxycarbonyloxycarbonyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-carbonyl)amino]ethyl]boronicacid (+) pinanediol ester in place of[(1R)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-[(2-isoindolin-5-ylacetyl)amino]ethyl]boronicacid (+) pinanediol ester. Purification was by reverse phase HPLC(Phenomenex Luna; 5 micron C18 column; 35×75 mm; flow rate 40 ml/mineluted with 5-40% CH₃CN/H₂O/0.1% TFA over 8 min). Purified fractionswere isolated by lyophilization. ESI-MS m/z 354 (MH)⁺.

Example 51:(R)-2-Hydroxy-3-(2-1,2,3,4-tetrahydro-isoquinolin-7-yl-acetylamino)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of7-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethylcarbamoyl]-methyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and 2-Boc-1,2,3,4-tetrahydro-7-isoquinolineaceticacid following the procedure described in Step 1 of Example 1. The crudeproduct was purified by flash chromatography on silica gel(EtOAc:Hexane, 25-100%). ESI-MS m/z 703 (MH)⁺.

Step 2. Synthesis of(R)-2-Hydroxy-3-(2-1,2,3,4-tetrahydro-isoquinolin-7-yl-acetylamino)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from7-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethylcarbamoyl]-methyl}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester and HCl following the procedure described in Step6 of Example 48. The crude product was purified by reverse phasepreparative HPLC and dried using lyophilization. ESI-MS m/z 381 (MH)⁺.

Example 52:(R)-2-Hydroxy-3-[(oxazole-5-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of2-Methoxy-3-[2-[(oxazole-5-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-benzoicacid tert-butyl ester

Prepared from2-methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-ylmethyl)-benzoicacid tert-butyl ester and oxazole-5-carboxylic acid following theprocedure described in Step 1 of Example 1. The crude product waspurified by flash chromatography on silica gel (EtOAc:Hexane, 10-100%).ESI-MS m/z 525 (MH)⁺.

Step 2. Synthesis of(R)-2-Hydroxy-3-[(oxazole-5-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Aluminum chloride (0.132 g, 0.990 mmol) was added to a solution of2-Methoxy-3-[2-[(oxazole-5-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)-ethyl]-benzoicacid tert-butyl ester (0.064 g, 0.122 mmol) in CH₂C12 (3.0 mL). Thereaction was stirred at room temperature for 16 hr. The reaction wasquenched with H₂O and CH₃OH and extracted with hexane (2×). The crudeproduct remained in the aqueous layer and was purified by reverse phasepreparative HPLC and dried using lyophilization. ESI-MS m/z 303 (MH)⁺.

Example 53:(R)-3-(2-carboxybenzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis oftert-butyl3-((2R)-2-(1,3-dioxoisoindolin-2-yl)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

To[(1S)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-chloro-ethyl]boronicacid (+) pinanediol ester (1.3 g from Step 9, Example 36) in 10 mL DMSOwas added potassium phthalimide (1.2 g). The resulting reaction mixturewas stirred at room temperature for 4 hr. Water was added to thereaction solution and extracted with EtOAc. The organic phase was driedand concentrated to afford the title product (1.8 g).

Step 2. Synthesis of(R)-3-(1,3-dioxoisoindolin-2-yl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared fromtert-butyl3-((2R)-2-(1,3-dioxoisoindolin-2-yl)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3.ESI-MS m/z 338 (MH)⁺.

Step 3. Synthesis of(R)-3-(2-carboxybenzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

To 20 mg of(R)-3-(1,3-dioxoisoindolin-2-yl)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid in a mixture of methanol and H₂O (2 mL, 1:1) was added 1 N NaOH(0.5 mL) and the resulting reaction mixture was stirred at roomtemperature for 3 hr. 1N HCl was added to adjust the pH of the solutionto 3. The product was then purified by reverse phase HPLC and driedusing lyophilization. ESI-MS m/z 356 (MH)⁺.

Example 54:(R)-3-(2-(2-aminoethylcarbamoyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis oftert-butyl3-((2R)-2-(2-(2-(tert-butoxycarbonylamino)ethylcarbamoyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Totert-butyl3-((2R)-2-(1,3-dioxoisoindolin-2-yl)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate(100 mg from Step 1, Example 53) in 2 mL methanol was added tert-butyl2-aminoethylcarbamate (1.1 eq). The resulting reaction mixture wasstirred at reflux for 2 hr. Methanol was then removed under reducedpressure. The crude product was used in the next step without furtherpurification.

Step 2. Synthesis of(R)-3-(2-(2-aminoethylcarbamoyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared fromtert-butyl3-((2R)-2-(2-(2-(tert-butoxycarbonylamino)ethylcarbamoyl)benzamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Theproduct was then purified by reverse phase HPLC and dried usinglyophilization. ESI-MS m/z 398 (MH)⁺.

Example 55:(R)-3-(4-(aminomethyl)-3-((isopropylamino)methyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-3-(4-(aminomethyl)-3-((isopropylamino)methyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

To(R)-3-(3,4-bis(aminomethyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid from Example 14 (44.1 mg) in methanol (2 mL) was added TEA (0.042mL), AcOH (0.050 mL), acetone (0.030 mL), and sodiumtriacetoxyborohydride (70 mg). The resulting reaction mixture wasstirred at room temperature for overnight. After removal of thesolvents, the product was then purified by reverse phase HPLC and driedusing lyophilization. ESI-MS m/z 412 (MH)⁺.

Example 56:(R)-3-(3,4-bis((isopropylamino)methyl)benzamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

The product was prepared in the same reaction described in Example 55.The product was purified by reverse phase HPLC and dried usinglyophilization. ESI-MS m/z 454 (MH).

Example 57:(R)-3-(2-(4-(2-aminoethylamino)phenyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of2-(4-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)phenyl)acetic acid

To 2-(4-aminophenyl)acetic acid (600 mg) in methanol (10 mL) was addedtert-butyl2-oxoethylcarbamate (800 mg) and sodium triacetoxyborohydride(1.3 g). The resulting reaction mixture was stirred at room temperatureovernight. The solvent was them removed under reduced pressure. Waterwas then added and extracted with EtOAc. The organic phase was dried andconcentrated. The residue was dissolved in 20 mL dioxane and 20 mL H₂O.To this solution was added di-tert-butyl dicarbonate (1.3 g) and Na₂CO₃(936 mg). The resulting reaction mixture was stirred at room temperaturefor overnight. After removal of the solvent, the residue was purified byreverse phase chromatography to afford the acid (0.5 g).

Step 2. Synthesis of tert-butyl3-((2R)-2-(2-(4-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)phenyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Prepared from[(1S)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-chloro-ethyl]boronicacid (+) pinanediol ester and2-(4-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)phenyl)aceticacid following the procedure described in step 10 of Example 36. Thecrude product was purified by flash chromatography on silica gel(Hexane/EtOAc, 2:1 to 1:2). ESI-MS m/z 806.1 (MH)⁺.

Step 3. Synthesis of(R)-3-(2-(4-(2-aminoethylamino)phenyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared fromtert-butyl3-((2R)-2-(2-(4-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)phenyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 384 (MH)⁺.

Example 58:(R)-3-(2-(3,4-bis(2-aminoethoxy)phenyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of2-(3,4-bis(2-(tert-butoxycarbonylamino)ethoxy)phenyl)acetic acid

To methyl 2-(3,4-dihydroxyphenyl)acetate (1.0 g) in DMF (10 mL) wasadded tert-butyl2-bromoethylcarbamate (2.7 g) and K₂CO₃ (1.7 g). Theresulting reaction mixture was stirred at 60° C. overnight. Water wasadded and the aqueous phase extracted with EtOAc. The organic phase wasthen dried and concentrated. The residue was purified by flashchromatography. The product was obtained as a mixture of mono- andbis-alkylation. The mixture was then dissolved in MeOH and THF (10 mL,1:1) and 1N NaOH was added. The resulting reaction mixture was stirredat room temperature overnight. 1N HCl was added to acidify the solution.The aqueous phase was extracted with EtOAc (3×). The organic phases werecombined, dried and concentrated. The title product was obtained byreverse phase chromatography purification (0.5 g).

Step 2. Synthesis oftert-butyl3-((2R)-2-(2-(3,4-bis(2-(tert-butoxycarbonylamino)ethoxy)phenyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Prepared from[(1S)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-chloro-ethyl]boronicacid (+) pinanediol ester and2-(3,4-bis(2-(tert-butoxycarbonylamino)ethoxy)phenyl)acetic acidfollowing the procedure described in step 10 of Example 36. The productwas purified by flash chromatography on silica gel (Hexane/EtOAc, 2:1 to1:2).

Step 3. Synthesis of(R)-3-(2-(3,4-bis(2-aminoethoxy)phenyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from tert-butyl3-((2R)-2-(2-(3,4-bis(2-(tert-butoxycarbonylamino)ethoxy)phenyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 444 (MH)⁺.

Example 59:(R)-3-(2-(4-(2-aminoethoxy)-3-hydroxyphenyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Synthesis of(R)-3-(2-(4-(2-aminoethoxy)-3-hydroxyphenyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

2-(4-(2-(tert-butoxycarbonylamino)ethoxy)-3-hydroxyphenyl)acetic acidwas prepared from the reaction described in Step 1, Example 58.(R)-3-(2-(4-(2-aminoethoxy)-3-hydroxyphenyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid was obtained following the procedure described in Steps 2 and 3,Example 58. The product was purified by reverse phase preparative HPLCand dried using lyophilization. ESI-MS m/z 401 (MH)⁺.

Example 60:(R)-3-(2-(6-(2-aminoethylamino)pyridin-3-yl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of methyl 2-(6-chloropyridin-3-yl)acetate

To a stirred solution of MeOH (25 mL) was added slowly acetyl chloride(3.5 mL). After 30 min, 2-(6-chloropyridin-3-yl)acetic acid (2.5 g) wasadded and the resulting reaction mixture stirred at room temperature for2 hr. Solvents were then removed. The residue was dissolved in EtOAc andwashed with 10% NaHCO₃. The organic phase was dried and concentrated toafford the product (2.5 g).

Step 2. Synthesis of 2-chloro-5-(2-methoxy-2-oxoethyl)pyridine 1-oxide

To methyl 2-(6-chloropyridin-3-yl)acetate (2.5 g) in DCM (100 mL) wasadded mCPBA (4.6 g). The resulting reaction mixture was stirred at roomtemperature for 4 hr. The organic phase was washed with sat. NaHCO₃,dried over Na₂SO₄, and concentrated. The crude product was purified byflash chromatography to afford the title product (2.5 g).

Step 3. Synthesis2-(2-(tert-butoxycarbonylamino)ethylamino)-5-(2-methoxy-2-oxoethyl)pyridine1-oxide

To 2-chloro-5-(2-methoxy-2-oxoethyl)pyridine 1-oxide (2.5 g) in t-BuOH(50 mL) was added DIEA (3.4 mL) and tert-butyl 2-aminoethylcarbamate(3.0 g). The resulting reaction mixture was stirred at 80° C. for 2days. The solvent was then removed and the residue purified by reversephase chromatography to afford the desired product (1.3 g).

Step 4. Synthesis of2-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)-5-(2-methoxy-2-oxoethyl)pyridine1-oxide

To2-(2-(tert-butoxycarbonylamino)ethylamino)-5-(2-methoxy-2-oxoethyl)pyridine1-oxide (1.3 g) in DCM (20 mL) was added di-tert-butyl dicarbonate (1.7g), TEA (1.2 mL), and DMAP (0.1 mg). The resulting reaction mixture wasstirred at room temperature for overnight. The solvent was removed andthe residue was used in the next step without further purification.

Step 5. Synthesis of2-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)-5-(carboxymethyl)pyridine1-oxide

To2-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)-5-(2-methoxy-2-oxoethyl)pyridine1-oxide from step 4 in a mixture of MeOH/THF (20 mL, 1:1) was added 1 NNaOH The reaction mixture was stirred at room temperature overnight. 1NHCl was added to acidify the solution to pH 4. The aqueous phase wasextracted with EtOAc (3×). The combined organic phases were dried andconcentrated. The residue was then purified by reverse phasechromatography to afford the product (1.4 g).

Step 6. Synthesis of2-(6-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)pyridin-3-yl)aceticacid

To2-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)-5-(carboxymethyl)pyridine1-oxide (0.78 g) in a mixture of THF (10 mL) and sat. NH₄Cl (10 mL) wasadded Zinc dust (0.65 g). The reaction mixture was stirred at roomtemperature for overnight. EtOAc was then added and washed with water.The organic phase was dried and concentrated to afford the desiredproduct (0.5 g).

Step 7. Synthesis oftert-butyl3-((2R)-2-(2-(6-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)pyridin-3-yl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Prepared from[(1S)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-chloro-ethyl]boronicacid (+) pinanediol ester and2-(6-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)pyridin-3-yl)aceticacid following the procedure described in Step 10 of Example 36. Thecrude product was purified by flash chromatography on silica gel. ESI-MSm/z 807.1 (MH)⁺.

Step 8. Synthesis of(R)-3-(2-(6-(2-aminoethylamino)pyridin-3-yl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared fromtert-butyl3-((2R)-2-(2-(6-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)pyridin-3-yl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 385 (MH)⁺.

Example 61:(R)-2-(2-aminoethylamino)-5-(2-(8-carboxy-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-3-ylamino)-2-oxoethyl)pyridine1-oxide

Synthesis of(R)-2-(2-aminoethylamino)-5-(2-(8-carboxy-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinin-3-ylamino)-2-oxoethyl)pyridine1-oxide

Prepared from2-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)-5-(carboxymethyl)pyridine1-oxide (step 5, Example 60) following the same procedure described inSteps 7 and 8, Example 60. The product was purified by reverse phasepreparative HPLC and dried using lyophilization. ESI-MS m/z 401 (MH)⁺.

Example 62:(R)-3-(5,6-bis(aminomethyl)nicotinamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Step 1. Synthesis of 5,6-bis((tert-butoxycarbonylamino)methyl)nicotinicacid

To methyl 5-bromo-6-chloronicotinate (1.1 g) in a flask was addedpotassium t-butoxycarbonyl amino methyl trifluoroborate (2.2 g), K₂CO₃(3.62 g), and XPhos-Pd-G2 (500 mg). The mixture was flushed with argonthree times. A mixture of t-BuOH and H₂O (18 mL, 1:1) was added. Thereaction mixture was stirred at 80° C. for overnight. The reaction wasdiluted with EtOAc. The organic phase was washed with water and brine,dried, and concentrated. The product was obtained by flashchromatography on silica gel to afford methyl5,6-bis((tert-butoxycarbonylamino)methyl)nicotinate (0.1 g). The esterwas hydrolyzed to acid following the procedure described in Step 5,Example 60.

Step 2. Synthesis of tert-butyl3-((2R)-2-(5,6-bis((tert-butoxycarbonylamino)methyl)nicotinamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate.tert-butyl3-((2R)-2-(2-(6-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)pyridin-3-yl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoate

Prepared from[(1S)-2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-chloro-ethyl]boronicacid (+) pinanediol ester and5,6-bis((tert-butoxycarbonylamino)methyl)nicotinic acid following theprocedure described in Step 10 of Example 36. The crude product waspurified by flash chromatography on silica gel. ESI-MS m/z 793.1 (MH)⁺.

Step 3. Synthesis of(R)-3-(5,6-bis(aminomethyl)nicotinamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid

Prepared from tert-butyl3-((2R)-2-(5,6-bis((tert-butoxycarbonylamino)methyl)nicotinamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^(2,6)]dec-4-yl)ethyl)-2-methoxybenzoateand BCl₃ following the procedure described in Step 2 of Example 3. Thecrude product was purified by reverse phase preparative HPLC and driedusing lyophilization. ESI-MS m/z 371 (MH)⁺.

TABLE 1 Examples of compounds ESI-MS Example Structure MW (m/z) for[MH]⁺ 1

351 352 2

361 362 3

394 395 4

372 373 5

366 367 6

386 387 7

380 381 8

351 352 9

352 353 10

366 367 11

395 396 12

343 344 13

381 382 14

369 370 15

380 381 16

394 395 17

394 395 18

383 384 19

397 398 20

383 384 21

469 470 22

426 427 23

340 341 24

388 389 25

453 454 26

350 351 27

388 389 28

362 363 29

363 364 30

350.1 351 31

350.1 351 32

350.1 351 33

366.1 357 34

351.1 352 35

351.1 352 36

366.1 367 37

408.2 409 38

357.1 358 39

343.1 344 40

386.1 387 41

393.2 394 42

393.2 394 43

364.1 365 44

369.1 370 45

453.2 454 46

364.2 365 47

377.2 378 48

380.2 381 49

409.2 410 50

353.1 354 51

380.2 381 52

302.0 303 53

355.1 356 54

397.2 398 55

411.2 412 56

453.2 454 57

383.2 384 58

443.2 444 59

400.2 401 60

384.2 385 61

400.2 401 62

370.1 371 63

370.1 64

370.1 65

384.2 66

384.2 67

384.2 68

410.2 69

409.2 70

437.2 71

402.1 72

388.1 73

452.2 74

488.2 75

401.2 76

387.1 77

383.2 78

369.1 79

369.1 80

383.2 81

383.2 82

367.2 83

381.2 84

367.2 85

381.2

Example 86: Parenteral Composition of a Compound of Formula I or FormulaIa

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a compound of Formula I orFormula Ia, or a water soluble pharmaceutically acceptable salt thereof,is dissolved in DMSO and then mixed with 10 ml of 0.9% sterile salinesolution. The mixture is incorporated into a dosage unit suitable foradministration by injection.

Example 87: Oral Composition of a Compound of Formula I or Formula Ia

To prepare a pharmaceutical composition for oral delivery, 400 mg of acompound of Formula I or Formula Ia and the following ingredients aremixed intimately and pressed into single scored tablets.

Tablet Formulation Quantity per tablet Ingredient mg compound 400cornstarch 50 croscamellose sodium 25 lactose 120 magnesium stearate 5

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Capsule Formulation Quantity per capsule Ingredient mg compound 200lactose spray dried 148 magnesium stearate 2

Biological Examples Example I: Experimental Method for β-LactamaseEnzyme Assays

Isolation of β-Lactamases.

For SHV-5, Kpc-2, p99AmpC and OXA-1 β-lactamases, E. coli BL21(DE3)bacterial cells carrying expression plasmids (expressed as nativeuntagged proteins) for the individual β-lactamases were grown in 1 L ofSuperbroth (Teknova Inc. Hollister, Calif.) supplemented with 100 μg/mlkanamycin selection and 1×5052 (0.5% glycerol, 0.05% glucose and 0.2%α-lactose) at 35° C. for 18-20 hours. Cells were harvested bycentrifugation (4,000×g, 4° C., 20 min), resuspended in 50 ml of 10 mMHEPES pH 7.5 (1/20 of the initial volume). The cells were lysed bysonication (5 pulses of 45 seconds) at 45 Won ice. The lysates wereclarified by centrifugation at 10,000×g for 40 minutes at 4° C. Sampleswere diluted 5-fold in 50 mM sodium acetate pH 5.0, stored overnight at4° C., after which they were centrifuged at 10,000×g for 30 minutes toclarify, and filtered through 0.45 μm filters. The samples were loadedonto a 5 ml Capto S sepharose cation exchange column (GE Healthcare)pre-equilibrated with 50 mM sodium acetate pH 5.0. The column was washedwith 5 column volumes of 50 mM sodium acetate pH 5.0 to wash out unboundprotein and a linear gradient of NaCl (0 to 500 mM) was used to elutethe protein (over 16 CV) from the column. Fractions were assayed forβ-lactamase activity using Centa (Calbiochem, Gibbstown, N.J.) orNitrocefin (EMD Millipore chemicals, Darmstadt, Germany) as a reporterβ-lactamase substrate for activity in the isolated fractions. Activefractions were pooled, concentrated and further purified by gelfiltration chromatography on a Superdex 75 prep grade gel filtrationcolumn (GE Healthcare, Piscataway, N.J.) pre-equilibrated in 50 mM HepespH 7.5, 150 mM NaCl. Active fractions were pooled concentrated,quantitated by BCA protein determination (Thermo Scientific, Rockford,Ill.), dialyzed into PBS and frozen at −80° C. in 20% glycerol untiluse.

For Vim-2 metallo β-lactamase, the procedure was identical with thefollowing exceptions, first the protein was not pH adjusted to pH 5 with50 mM sodium acetate, second, the chromatography step was changed to a 5ml Q sepharose anion exchange column pre-equilibrated with 50 mM HepespH 7.5, and elution of the protein was achieved by a linear gradient ofNaCl (0-600 mM). Finally, the VIM-2 purification required a second run(3^(rd) step) on the Q sepharose anion exchange column to achieveacceptable purity (>90%). 3-Lactamase Inhibition.

To determine the level of inhibition of β-lactamase enzymes, compoundswere diluted in PBS at pH 7.4 to yield concentrations ranging from 100to 0.00005 μM in 96-well microtiter plates. An equal volume of dilutedenzyme stock was added, and the plates were incubated at 37° C. for 15min. Nitrocefin was used as substrate for p99 AmpC, VIM-2 and OXA-1 anddispensed into each well at a final concentration of 100 μM. Absorbanceat 486 nm was immediately monitored for 10 min using a Biotek PowerwaveXS2 microplate spectrophotometer using the GEN5 software package (BiotekInstruments, Winooski Vt.). In an analogous fashion, imipenem was usedas substrate for Kpc-2 and Cefotaxime was used for SHV-5, while changesin absorbance upon hydrolysis of the β-lactam ring were monitored at 300nm and 260 nm respectively in UV-transparent 96-well microtiter assayplates. Maximum rates of hydrolysis were compared to those in controlwells (without inhibitors), and percentages of enzyme inhibition werecalculated for each concentration of inhibitor. The concentration ofinhibitor needed to reduce the initial rate of hydrolysis of substrateby 50% (IC₅₀) was calculated as the residual activity of β-lactamase at486 nm using GraFit version 7 kinetics software package (ErithacusSoftware, Surrey, UK).

Example II: Inhibition of Diverse β-Lactamases by Exemplary Compounds

Using the methodology described above, examples of the current inventionwere evaluated for their ability to inhibit β-lactamase enzymes from allfour Ambler classifications (A through D). The results of these assaysare summarized in Table 2 for representative enzymes across differentsubtypes (note SHV-5 represents an Ambler Class A Extended Spectrumβ-Lactamases, KPC-2 exemplifies a Class A carbapenemase, P99 representschromosomal Class C AmpC, OXA-1 represents a Class D oxacillinase andVIM-2 represents a class B zinc-dependent metallo-β-lactamase alsopossessing carbapenemase activity), where A represents an IC₅₀ of 10-100μM, B represents an IC₅₀ of 1 to 10 μM, C represents an IC₅₀ of 0.1 to 1μM, and D represents an IC₅₀ of <0.1 μM. NT=Not tested.

TABLE 2 Inhibition of Diverse β-Lactamases by Exemplary Compounds ClassA Class B Class C Class D EXAMPLE SHV-5 KPC-2 VIM-2 AmpC OXA-1 1 D D C DD 2 D D B D D 3 A D B D C 4 D D C D D 5 D D C D D 6 D D B D D 7 D D C DC 8 D C B D NT 9 D D D D D 10 D D D D D 11 D D C D D 12 D D C D D 13 D CB D D 14 C C D D D 15 D C B D C 16 D D D D D 17 D D D D D 18 D D C D D19 D D D D D 20 D D D D D 21 C D D D D 22 B C C D D 23 D D C D D 24 D DC D D 25 C D D D C 26 D D C D D 27 D D B D D 28 D D B D D 29 D D B D D30 C D C D D 31 C D B D D 32 D D C D D 33 D D C D D 34 D D C D D 35 D DC D D 36 D D C D D 37 D D C D D 38 D D C D D 39 C D C D D 40 C D D D D41 D D D D D 42 D D C D D 43 C D C D D 44 B B B C B 45 C D D D D 46 D DD D D 47 D D C D D 48 D D D D D 49 D D C D D 50 D D C D D 51 D D D D D52 D D C D D 53 C C B D D 54 C C B D B 55 C B C C C 56 D D C D D 57 D DB D D 58 D D C D D 59 D D C D D 60 D D C D D 61 D D C D D 62 D D C D D63 C D D D D

Example III: In vitro Antibacterial Assays of β-Lactamase Inhibition

To determine the ability of test compounds to potentiate the inhibitionof the growth of bacterial strains that produce beta-lactamase enzymes,classic cell based broth microdilution MIC assays were employed. Sixbacteria strains producing beta-lactamase enzymes were used: E. coliexpressing the Class A Extended Spectrum Beta-Lactamase (ESBL) CTX-M-15,E. cloacae expressing the Class C P99, K. pneumoniae expressing theClass A carbapenemase KPC-2, P. aeruginosa expressing the Class Bcarbapenemase VIM-2, K. pneumoniae expressing the class A carbapenemaseKPC-2 and the class B carbapenemase VIM-4, and S. aureus producing theClass A penicillinase PC-1. The assay was conducted in Cation AdjustedMueller Hinton Broth (CAMHB, BD #212322, BD Diagnostic Systems, Sparks,Md.). Bacteria strains were grown for 3-5 hours in CAMBH broth. Testcompounds were added to a microtiter plate in 2-fold serial dilutions inCAMHB in a final concentration range of 32 μg/mL to 0.25 μg/ml. Anoverlay of CAMHB containing a Beta-lactam was added to the compounds ata final static concentration of 4 μg/ml. Ceftazidime (CAZ, Sigma #C3809-1G, Sigma-Aldrich, St. Louis, Mo.) was used as the partnerantibiotic for E. coli expressing Ambler Class A ESBL CTX-M-15 (MICalone >128 μg/ml), and E. cloacae expressing Class C P99 (MIC alone=128μg/mL). Meropenem (Mero, USP #1392454, U.S. Pharmacopeia, Rockville,Md.) was used as the partner antibiotic for K. pneumoniae expressingAmbler Class A carbapenemase KPC-3 (MIC alone >128 μg/mL), P. aeruginosaexpressing Class A carbapenemase VIM-2 (MIC alone=16 μg/mL), and K.pneumoniae expressing the Ambler Class A carbapenemase KPC-2 and AmblerClass B carbapenemase VIM-4 (MIC alone=64 μg/mL). Piperacillin (Pip,Fisher # ICN15626801, MP Biomidicals, Solon, Ohio) was used as thepartner antibiotic for S. aureus producing the Class A penicillinasePC-1 (MIC alone=64 μg/ml). Titration of test compounds with MIC readoutindicates the concentration of test article needed to sufficientlyinhibit beta-lactamase enzyme activity and protect the intrinsicantibacterial activity of the beta-lactam. In addition to the titrationof test compounds the MICs of a panel of control beta-lactams is alsotested to ensure the strains are behaving consistently from test totest. Once the test compound and antibiotics are added the plates can beinoculated according to CLSI broth microdilution method. Afterinoculation the plates are incubated for 16-20 hours at 37° C. then theMinimal Inhibitory Concentration (MIC) of the test compound isdetermined visually.

Example IV: In vitro Antibacterial Activity of Exemplary Compounds

Using the methodology described above in EXAMPLE III, exemplarycompounds for Formula I or Formula Ia were evaluated for their abilityto inhibit the growth of β-lactamase producing bacteria in the presenceof a β-lactam antibiotic.

Representative results are shown in Table 3 where A represents an MIC ofthe fixed β-lactam antibiotic in the presence of >32 μg/mL of aβ-lactamase inhibitor of exemplary compounds, B represents the MIC inthe presence of between 8 and 32 μg/mL of a β-lactamase inhibitor ofexemplary compounds, and C represents the MIC in the presence of <4μg/mL of a β-lactamase inhibitor of exemplary compounds. NT=Not Tested.

TABLE 3 Broad spectrum inhibition of bacterial growth. MIC of examplecompounds of the invention in the presence of a fixed amount (4 μg/mL)of designated β-lactam antibiotics ceftazidime (CAZ), meropenem (Mero),Piperacillin (Pip). MIC (μg/mL) of Exemplary Compounds in presence offixed β-lactams Fixed CAZ Fixed Mero ESBLs Carbapenemases (Class A andC) (Classes A and B) Fixed Pip E. cl. P. K.P. Penicillinase E. coli144200 K.P. aerug. A-1797 S. aureus EXAM- ESBL4 p99 156319 Ps296 KPC-2MSSA-7 PLE CTX-M-15 AmpC KPC-3 VIM-2 VIM-4 PC-1 1 C C B B 2 C C B B A C3 C C C B A A 4 C C C A C C 5 C C C A C C 6 C C C A B C 7 C C B A C C 8C C A C A C 9 C C C C C C 10 C C C B C C 11 C C C A C C 12 B C B A B C13 C C C B B C 14 C C C C C C 15 C C B C B C 16 C C C C C C 17 C C C B CC 18 C C C C C C 19 C C C C C C 20 C C C C C C 21 C C B A B B 22 C C C AB C 23 C C C B B C 24 C C B B B C 25 C C C C C C 26 C C C B B C 27 C C AA A C 28 C C C A B C 29 C C C A A C 30 C C C C B C 31 C C C B A C 32 C CC C A C 33 C C C C B C 34 C C C C B C 35 C C C C A C 36 C C C C A C 37 CC C C A C 38 C C C B B C 39 C C C B B B 40 C C C C C C 41 C C A B C C 42C C A C B C 43 C C A A A C 44 B A A A A A 45 C C C C C A 46 C C C C C B47 C C C B A C 48 C C C C C C 49 C C C C A C 50 C C C C A C 51 C C C C CC 52 C C C B A C 53 C C C A B C 54 C C B C A A 55 C C B C A A 56 C C C CC C 57 C C B C C C 58 C C C C B C 59 C C C C B C 60 C C C C B C 61 C C CC C C 62 C C C C C C 63 C C C C C C

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A compound of Formula (I) or Formula (Ia), apharmaceutically acceptable salt, polymorph, solvate, prodrug, N-oxide,or isomer thereof:

wherein: M is a bond; m is 0, 1, or 2; n is 0, 1, 2, or 3; p is 3; X¹and X² are independently selected from —OH, —OR⁸, or F; Z is >C═O, >C═S,or >SO₂; ArA is an optionally substituted aromatic or 6-memberedheteroaromatic ring system; each Y is selected from the group consistingof fluoro, chloro, —CN, optionally substituted C₁-C₆ alkyl, —OH,—OR¹⁰,—NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—O(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —C(O)NR⁴(CR⁶R⁷)_(v)NR 4R⁵,—S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—OC(O)NR⁴(CR⁶R⁷)_(v) NR⁴R⁵, —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵) R⁶,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—(CR⁶R⁷)_(v)C(═NR⁵)NR ⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵) NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵, —C (═NR⁴)NR⁴R⁵,—C(═NR⁴)NR⁴C(O)R⁶, —NR⁴S⁰²R⁶, —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O) NR⁴R⁵,—(CR⁶R⁷)_(v)C(O)NR⁴R⁵, -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,-Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,—N(R⁴)—Heteroaryl-NR⁴R⁵, —N(R⁴)-Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl,—(CR⁶R⁷)_(v)Heterocyclyl, —O-Heteroaryl, —O-Heterocyclyl,—NR⁴(CR⁶R⁷)_(v)Heteroaryl, —NR⁴(CR⁶R⁷)_(v)Heterocyclyl,—O(CR⁶R⁷)_(v)Heteroaryl, —O(CR⁶R⁷)_(v)Heterocyclyl, and —O(CR⁶R⁷)_(v)O-Heterocyclyl; v is 1-4; R^(a), R^(b), and R^(C) are independentlyselected from the group consisting of hydrogen, fluoro, chloro, bromo,optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OH, —OR¹⁰, —NR⁴R⁵, and —SR¹⁰;R¹ and R² are independently selected from the group consisting ofhydrogen, fluoro, chloro, bromo, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, and —NR⁴R⁵,or R¹ and R² taken together form an oxo, oxime, or an optionallysubstituted carbocycle or optionally substituted heterocycle with thecarbon to which they are attached; R³ is hydrogen, optionallysubstituted C₁-C₆ alkyl, or a pharmaceutically acceptable prodrug;R^(d), R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, —OH, —CN, optionally substituted C₁-C₆ alkyl, optionallysubstituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionallysubstituted aminoalkyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclylalkyl, optionally substitutedaralkyl, optionally substituted heteroaralkyl,(poly-ethylene-glycol)-ethyl, and an optionally substituted saccharide;or R⁴ and R⁵ taken together form an optionally substituted heterocyclewith the nitrogen to which they are attached; R⁶ and R⁷ areindependently selected from the group consisting of hydrogen, fluoro,chloro, bromo, optionally substituted C₁-C₆ alkyl, optionallysubstituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionallysubstituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵,—C(O)NR⁴R⁵, —NR⁴SO₂R⁵, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or R⁶ and R⁷taken together form an oxo, oxime, or an optionally substitutedcarbocycle or an optionally substituted heterocycle with the carbon towhich they are attached; R⁸ is optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₆ cycloalkyl, or a pharmaceuticallyacceptable boronate ester group; and R¹⁰ is optionally substituted C₁-C₆alkyl or optionally substituted C₃-C₆ cycloalkyl.
 2. The compound ofclaim 1, wherein R^(a), R^(b), and R^(C) are independently hydrogen,fluoro, or chloro.
 3. The compound of claim 2, wherein R^(a), R^(b), andR^(c) are hydrogen.
 4. The compound of claim 1, wherein R³ is hydrogen.5. The compound of claim 1, wherein X¹ and X² are —OH.
 6. The compoundof claim 1, wherein R^(d) is hydrogen or C₁-C₄-alkyl.
 7. The compound ofclaim 1, wherein Z is >C═0.
 8. The compound of claim 1, wherein: M is abond; and m and n are
 0. 9. The compound of claim 1, wherein: M is abond; and m or n are
 1. 10. The compound of claim 1, wherein each R¹ andR² are independently selected from the group consisting of fluoro,chloro, bromo, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, and —NR⁴R⁵, or R¹ andR² taken together form an oxo, oxime, or an optionally substitutedcarbocycle or optionally substituted heterocycle with the carbon towhich they are attached.
 11. The compound of claim 1, wherein ArA isbenzene.
 12. The compound of claim 1, wherein ArA is selected from thegroup consisting of benzene, pyridine, or pyrimidine.
 13. The compoundof claim 1, wherein at least one Y is selected from the group consistingof fluoro, chloro, —CN, optionally substituted C₁-C₆ alkyl, —OH,—OR¹⁰,—NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—O(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(═NR⁵)R⁶,—(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —O(CR⁶R ⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴) NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵,—C(═NR⁴)NR⁴C(O)R⁶, —NR⁴SO₂R⁶, —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O)NR⁴R⁵, and—(CR⁶R⁷)_(v)C(O)NR⁴R⁵.
 14. The compound of claim 1, wherein at least oneY is selected from the group consisting of fluoro, chloro, —CN,optionally substituted C₁-C₆ alkyl, —OH, —OR¹⁰,—NR⁴R⁵,—(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵,—N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,—C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR ⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, and—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶.
 15. The compound of claim 1, wherein R⁴and R⁵ are independently hydrogen or optionally substituted C₁-C₆ alkyland each R⁶ and R⁷ are independently hydrogen, fluoro, or optionallysubstituted C₁-C₆ alkyl.
 16. The compound of claim 15 wherein each R⁴and R⁵ is hydrogen and each R⁶ and R⁷ are hydrogen.
 17. The compound ofclaim 1, wherein v is
 1. 18. A pharmaceutical composition comprising acompound of claim 1 or a pharmaceutically acceptable salt, polymorph,solvate, prodrug, N-oxide, or isomer thereof, and a pharmaceuticallyacceptable excipient.
 19. The pharmaceutical composition of claim 18,further comprising a beta-lactam antibiotic.
 20. A method of treating abacterial infection in a subject, comprising administering to thesubject a pharmaceutical composition of claim 18, optionally incombination with a beta-lactam antibiotic.